CN101432011A

CN101432011A - Methods for regulating neurotransmitter systems by inducing counteradaptations

Info

Publication number: CN101432011A
Application number: CNA2007800151175A
Authority: CN
Inventors: 亚历山大·米哈洛
Original assignee: Individual
Current assignee: Individual
Priority date: 2006-02-27
Filing date: 2007-02-27
Publication date: 2009-05-13

Abstract

The present invention relates to methods for regulating neurotransmitter systems by inducing a counteradaptation response. According to one embodiment of the invention, a method for regulating a neurotransmitter includes the step of repeatedly administering a ligand for a receptor in the neurotransmitter system, with a ratio of administration half-life to period between administrations of no greater than 1/2. The methods of the present invention may be used to address a whole host of undesirable mental, neurological and physiological conditions.

Description

Regulate the method for neurotransmitter system by inducing counter adaptation

The cross reference of related application

The application is U.S. Patent Application Serial Number 11/234 of JIUYUE in 2005 submission on the 23rd according to 35 U.S.C. § 120,850 part continuation application (continuation-in-part), and described 11/234,850 require JIUYUE in 2004 rights and interests that submit to, that be entitled as the U.S. Provisional Application 60/612,155 of " COUNTER-ADAPTATION THERAPY FOR TREATMENT OF DEPRESSIONAND OTHER MENTAL CONDITIONS " on the 23rd according to 35 U.S.C. § 119 (e) again.The application requires U.S. Provisional Patent Application serial number 60/777 that submit to, that be entitled as " METHOD OF REGULATINGTHE CRF AND AVP SYSTEMS BY INDUCING COUNTERADAPTATIONS " on February 27th, 2006, the priority of submitting on November 9th, 190 and 2006, be entitled as the U.S. Provisional Patent Application serial number 60/858,186 of " OPIATE ANATOGONISTS FOR COUNTERADAPTATION THERAPY ".The provisional application of above-mentioned reference is incorporated this paper into its integral body by reference at this.

Technical field

The present invention relates in general to the neurotransmitter system.The present invention relates more specifically to by inducing counter adaptive reaction (counteradaptative responses) to regulate the method for these neurotransmitter systems.

Background technology

Emotion, mood disorders and associated conditions are the results of the complex network of central nervous system's incident, and these central nervous system's incidents and many neurotransmitteies system are interrelated.Modal mood disorders is depressed.Depression is clinical diagnosis, and it has multiple body and mental symptom, and depression is that change owing to the various neurotransmitters system causes.Though the most frequent relevant neurotransmitter system is norepinephrine and 5-hydroxy tryptamine system with depression, present other system that studies show that, also relevant such as P material system, dynorphin (dynorphin) system (kappa receptor), endogenous endorphins (endophin) system (μ and delta opiate receptor), corticotropin-releasing factor (corticotropin releasing factor) system and arginine vasopressin (arginine vasopressin) system with depression.In addition, these neurotransmitter systems also with other bad spirit, neural relevant with the whole host of physiological disorder, comprise biphasic or bipolar type mental disorder (bipolar disorders), obsession (obsessive-compulsive disorder), anxiety (anxiety), phobia (phobia), stress disorders (stress disorder), psychoactive substance abuse (substance abuse), sexual dysfunction (sexual disorder), eating disorders (eating disorders), motivation obstacle (motivational disorders), pain obstacle (pain disorder), cardiovascular disorder (cardiovascular disorder), disease relevant (aging-related disorder) and the disease (immune-system related disorder) relevant with immune system with aging.

The conventional strategy of treatment neurotransmitter relevant disease concentrates on the unusual high or low level of improving the synapse neurotransmitter.The function of neurotransmitter system is directly regulated in the conventional therapy agent.Described medicament can be antianxiety drug, somnifacient or selectivity reuptake inhibithors, and comprise benzodiazepine

Class medicine (for example diazepam (diazepam), lorazepam (lorazepam), alprazolam (alprazolam), temazepam (temazepam), flurazepam (flurazepam) and chlordiazepoxide (chlodiazepoxide)), TCAs, MAOIs, SSRIs (for example, fluoxetine Hydrochloride (fluoxetine hydrochloride)), NRIs, SNRIs, CRF regulator, 5-hydroxy tryptamine presynaptic autoreceptor antagonist, 5HT ₁Agonist, GABA-A regulator, 5-hydroxy tryptamine 5H _2CAnd/or 5H _2BRegulator, β-3 adrenoceptor agonists, nmda antagonist, V1B antagonist, GPCR regulator, dynorphin antagonist and P substance antagonist.

Conventional therapy agent and method are though some effect has some shortcomings.For example, the use of many conventional therapy agent is with side effect, such as sexual dysfunction, feel sick, nervousness, fatigue, xerostomia, blurred vision and weight increase.In addition, the patient can or set up toleration to reusable conventional therapy agent generation, makes their effectiveness lose in time.

Summary of the invention

One aspect of the present invention relates to by inducing counter adaptation among the patient to regulate the method for neurotransmitter system, described neurotransmitter system comprises acceptor type, described method comprises: to the part of the described acceptor type of patient's repetitive administration, use at every turn and have the half life of using (administration half-life), thus with use the relevant very first time at every turn during make the receptors bind of described part and the type in (first time period), induce thus, keep or improve counter adaptation, wherein counter adaptation causes the adjusting to the neurotransmitter system, and wherein use half life and use between during the ratio of (period betweenadministrations) be not more than 1/2.

In an aspect of of the present present invention, the neurotransmitter system is the SP system; Acceptor type is the SP receptor; Described part is the SP receptor stimulating agent; And described counter adaptation causes reducing the SP system.

In another aspect of the present invention, the neurotransmitter system is an endogenous endorphins system; Acceptor type is μ and/or delta opiate receptor (mu and/or delta opiate receptors); Part is μ and/or delta opiate receptor agonist; And described counter adaptation causes the rise of endogenous endorphins system.

In another aspect of the present invention, the neurotransmitter system is the dynorphin system; Acceptor type is kappa receptor (kappa receptors); Part is the kappa receptor agonist; And described counter adaptation causes the downward modulation of dynorphin system.

In another aspect of the present invention, the neurotransmitter system is the 5-hydroxy tryptamine system; And described counter adaptation causes the rise of 5-hydroxy tryptamine system.Therefore, in the embodiment of this aspect of the present invention, acceptor type is the 5-hydroxy tryptamine presynaptic autoreceptor; And part is a 5-hydroxy tryptamine presynaptic autoreceptor agonist.In another embodiment of this aspect of the present invention, acceptor type is the 5-hydroxy tryptamine postsynaptic receptor; And part is a 5-hydroxy tryptamine postsynaptic autoreceptor antagonist.

In another aspect of the present invention, the neurotransmitter system is the norepinephrine system; And described counter adaptation causes the rise of norepinephrine system.Therefore, in the embodiment of this aspect of the present invention, acceptor type is a norepinephrine presynaptic alpha-2 adrenergic receptor; And part is a norepinephrine presynaptic alpha-2 adrenergic receptor agonists.Acceptor type is a norepinephrine postsynaptic adrenoreceptor in another embodiment of this aspect of the present invention; And part is a norepinephrine postsynaptic adrenergic aceptor antagonist.

In still another aspect of the invention, the neurotransmitter system is the CRF system; Acceptor type is the CRF receptor; Part is the CRF receptor stimulating agent; And counter adaptation causes the downward modulation of CRF system.

In still another aspect of the invention, the neurotransmitter system is the CRF system; Acceptor type is the CRF receptor; Part is the CRF receptor antagonist; And counter adaptation causes the rise of CRF system.

In still another aspect of the invention, the neurotransmitter system is the AVP system; Acceptor type is the AVP receptor; Part is the AVP receptor stimulating agent; And counter adaptation causes the downward modulation of AVP system.

In still another aspect of the invention, the neurotransmitter system is the AVP system; Acceptor type is the AVP receptor; Part is the AVP receptor antagonist; And counter adaptation causes the rise of AVP system.

In another embodiment of the present invention, the method of the adjusting of inducing the neurotransmitter system is provided, described neurotransmitter system comprises and bad spirit, nerve or physiological disorder (undesirable mental, neurological or physiological condition) relevant acceptor type, said method comprising the steps of: to the part of the described acceptor type of patient's repetitive administration, use at every turn and have the half life of using, thus with use the relevant very first time at every turn during in make most of receptors bind of described part and described acceptor type, induce counter adaptation thus, wherein counter adaptation with use the second relevant time durations at every turn in cause adjusting to the neurotransmitter system, described second time durations during the very first time after.

In still another aspect of the invention, method as herein described is used for the treatment of or disposes bad spirit, nerve or physiological disorder among the patient, the receptor relevant (linked to receptors of the type of receptor) of described bad spirit, nerve or physiological disorder and described acceptor type.

In still another aspect of the invention, method as herein described is used for the treatment of or disposes the disease relevant with immune system bad among the patient who needs it, the described disease relevant with immune system and the receptor of described acceptor type are correlated with, and described method causes immune rise.

In still another aspect of the invention, method as herein described is used in needs treatments or disposes the cardiovascular diseases or patient's treatment of the disease relevant with lipid or cholesterol metabolism or dispose described disease or disease, and described cardiovascular diseases or the disease relevant with lipid or cholesterol metabolism and the receptor of described acceptor type are correlated with

In still another aspect of the invention, method as herein described is used for the treatment of or disposes preparation deficiency to the sports in future.

In still another aspect of the invention, method as herein described is used for the treatment of or disposal and the relevant bad disease of Sirt1 approach (Sirt 1 pathway).

Method of the present invention causes the multiple advantage that is better than art methods.For example, the method for the present invention side effect that can be used for treating the whole host of (address) bad spirit, nerve and physiological disorder and have reduction.In embodiments more of the present invention, the arrangement of time of required treatment benefit can be consistent with the desirable time on daytime and the task of being carried out.

Further feature of the present invention and advantage will describe in detail hereinafter, and wherein some part to be those skilled in the art can understand easily or recognize by implementing description of the present invention and claim and the described invention of accompanying drawing from description.

Should understand aforementioned whole explanation and following description is of the present invention illustrating, and intention provides a summary or framework to be used to understand desired nature of invention and feature.

Be used in accompanying drawing is also contained in further understanding the present invention, and be included in the description as its part.Described accompanying drawing need not to amplify in proportion, and the size of various elements for the sake of clarity can change.Description of drawings one or more embodiments of the present invention, and explained principle of the present invention and operation with description together.

Description of drawings

Fig. 1 is the figure of ligand concentration (a part) and emotion (b part) in according to an embodiment of the invention the body;

Fig. 2 is according to another embodiment of the present invention, uses for several times under the situation of part emotion with respect to the figure of time;

Fig. 3 is that ligand concentration is with respect to the figure of time in the body by under the chemical compound relative situation that the single injection of long part is used of half life;

Fig. 4 is that ligand concentration is with respect to the figure of time in the body by under the chemical compound relative situation that time-delay-release (time-release) transdermal patch of short part is used of half life;

Fig. 5 is that ligand concentration is with respect to the figure of time in the body by under the chemical compound relative situation that time-delay-the release transdermal patch is used than short part of half life, and wherein said patch is removed in application; With

Fig. 6 is according to another embodiment of the invention, and ligand concentration (a part) and emotion (b part) are with respect to the figure of time in the body.

The specific embodiment

The present invention relates in general to by the exploitation patient neurotransmitter system is regulated in the reaction (" counter adaptation ") of medicament, rather than relies on the clinical effectiveness that the direct effect of medicament is improved.Generally speaking, select medicament to make counter adaptation useful and required long term effect finally is provided for the patient.Method of the present invention is that with the difference of conventional method the direct effect of described medicament is the adjusting to relevant with severity of symptoms usually neurotransmitter receptor.But respond to the direct effect of described medicament, nicergoline is crossed the counter adaptation generation and replied, thereby the required adjusting that when any direct effect of described medicament weakens gradually, has produced the neurotransmitter system.Described adjusting can be any change of neurotransmitter systemic-function, for example, and can be for raising or downward modulation.Directly inducing specific acute reaction (specific acute response) is with the required long term effect of indirect generation.In simple analogy, produced depression as glad stimulating type medicament such as M﹠C when the drug withdrawal, irritated stimulating type medicament has produced " antidepressant effect " when drug withdrawal.

One embodiment of the invention relate to the method for regulating the neurotransmitter system.Usually, the neurotransmitter system is the system of natural neurotransmitter chemical compound and synapse receptor, and this system participates in the transmission of central nervous system's signal.The neurotransmitter system comprises acceptor type.For example, described acceptor type can, relevant with bad spirit, nerve or physiological disorder.Fig. 1 comprises that ligand concentration is with respect to the figure of time in the body of method according to embodiments of the present invention.As shown in Figure 1, described method comprises the part to the described acceptor type of patient's repetitive administration, thus with use the relevant very first time at every turn during in make the step of receptors bind of described part and the type.As used herein, part is the chemical compound of the receptors bind (for example with covalently or non-covalently mode interact) in conjunction with described acceptor type, and for example can be the agonist of described receptor or the antagonist of described receptor.The zygotic induction counter adaptation of part and receptor, this causes the adjusting to the neurotransmitter system.Fig. 1 is presented at twice part that occurs in the middle of the described method and uses, and is not that the first two times is used.Use is single circulation at every turn, and wherein the bulk concentration of part begins at baseline, reaches top level, rolls back baseline then down.Fig. 1 illustrates described using twice.According to dosage, can be for example by giving single unit dose of patient (for example pill, capsule) or injection; A plurality of unit dose or injection; Or the mode of (for example intravenous or slow-release patch) is carried out at every turn using of part continuously.

Can implement the type of neurotransmitter system of described method and the example of acceptor type and comprise the P material system, its acceptor type can be NK-1, NK-2 and/or NK-3 receptor; Endogenous endorphins system, its acceptor type can be μ and/or delta opiate receptor; The dynorphin system, its acceptor type can be kappa receptor; The 5-hydroxy tryptamine system, its acceptor type can be inhibition 5-hydroxy tryptamine presynaptic autoreceptor (for example, 5HT _1AAnd/or 5HT _1BAutoreceptor) and/or 5-hydroxy tryptamine postsynaptic receptor (5HT for example ₁, 5HT ₂, 5HT ₃, 5HT ₄, 5HT ₅, 5HT ₆And/or 5HT ₇Receptor); The norepinephrine system, its acceptor type can be inhibition norepinephrine presynaptic alpha-2 adrenergic receptor and/or norepinephrine postsynaptic adrenoreceptor; Corticotropin-releasing factor (CRF) system, wherein acceptor type can be CRF receptor (for example CRF-1 receptor and/or CRF-2 receptor; And arginine vasopressin (AVP) system, wherein acceptor type can be AVP receptor (for example, V1R is also referred to as V1a, V2R and/or V3R, is also referred to as V1b).These neurotransmitter systems and acceptor type and multiple bad spirit, nerve are relevant with physiological disorder, and this is that those skilled in the art are intelligible.

In aspect more of the present invention, bad spirit, nerve or physiological disorder are relevant with acceptor type in the neurotransmitter system.If described bad spirit or nervous system disease, claim the receptor " positive correlation " of itself and described type so owing to receptor increases the weight of with combining of its natural neurotransmitter.Otherwise, if described bad spirit, nerve or physiological disorder are improved itself and described acceptor type " negative correlation " so with combining of its natural neurotransmitter by receptor.For example, depressed bad spirit, nerve or physiological disorder and 5-hydroxy tryptamine postsynaptic receptor negative correlation, this is because these receptors have caused depressed alleviating with their combining of natural neurotransmitter serotonin.Depressed bad spirit, nerve or physiological disorder and kappa receptor positive correlation, this is because these receptors have caused depressed increasing the weight of with combining of their natural mediator dynorphins.

Except depending on ligand-receptor in conjunction with to regulating the direct effect of neurotransmitter system, the indirect counter adaptation effect of method utilization of the present invention strengthens or suppresses the neurotransmitter system.Described counter adaptation is that brain is to the bonded natural response of part.The bonded initial effect of part can be the deterioration of bad spirit, nerve or the physiological disorder relevant with the neurotransmitter system.Yet, because the influence of described counter adaptation still continues the long period after part is removed from system, and can be along with the repetitive administration accumulation of part, counter adaptation causes the overall desirable regulation and control to the neurotransmitter system.The regulation and control of neurotransmitter system can provide the treatment benefit of described bad spirit, nerve or physiological disorder conversely.The regulation and control of neurotransmitter for example can be, counter adaptive increased response (shown in Figure 2, it is described to see below), or keep inductive counter adaptive reaction (shown in Figure 6, it is described to see below).

Counter adaptation is the mode that the central nervous system keeps dynamic equilibrium.Counter adaptation is that body is attempted the neurotransmitter system is adjusted to its incipient stability status level to prevent its overstimulation or to stimulate not enough.The time that natural neurotransmitter and its receptors bind are only short, and almost remove immediately from synapse, and do not cause the counter adaptive reaction thus.Yet, when long time of part and acceptor interaction (for example because part have long binding time or continue to use), cell mechanism engenders that in receptor/neurotransmitter levels it act as offsets the bonded direct effect of ligand-receptor (being counter adaptation).Counter adaptation can be, for example, change with the biosynthesis or the release of the bonded natural neurotransmitter of described acceptor type, change with the absorption again of the bonded natural neurotransmitter of described acceptor type, the number of the receptor of described acceptor type and/or the number of binding site change, the bonded sensitivity of the receptor of described acceptor type and natural neurotransmitter and/or receptor stimulating agent changes, or its any combination.The life-time service of part is induced (promptly causing) counter adaptation by stimulating course thus, and described stimulating course is opposite with the primary effect of part, and it causes the bonded effect of ligand-receptor to reduce in time.

If part is a receptor stimulating agent, the counter adaptation role is to make the miopragia (that is, " downward modulation ") of neurotransmitter.Described downward modulation for example can show as and the biosynthesis of the bonded natural neurotransmitter of described acceptor type or the minimizing of release, increase with the absorption again of the bonded natural neurotransmitter of described acceptor type, the decreased number of the binding site on the receptor of described acceptor type decreased number and/or described acceptor type, the receptor of described acceptor type pair reduces with the bonded sensitivity of natural neurotransmitter and/or receptor stimulating agent, or its any combination.Any above-mentioned counter adaptive reaction role is reduce the neurotransmitter system functional, and can provide thus with regard to the treatment benefit with regard to described neurotransmitter system positively related bad spirit, nerve and physiological disorder.

Otherwise, if part is a receptor antagonist, the counter adaptation role be to make the increased functionality (that is, " rise ") of neurotransmitter.Described rise for example can show as and the biosynthesis of the bonded natural neurotransmitter of described acceptor type or the increase of release, reduce with the absorption again of the bonded natural neurotransmitter of described acceptor type, the number of the binding site on the receptor of described acceptor type number increase and/or described acceptor type increases, the bonded sensitivity of the receptor of described acceptor type and natural neurotransmitter and/or receptor stimulating agent improves, or its any combination.Any above-mentioned counter adaptive reaction role be improve the neurotransmitter system functional, and can provide thus with regard to the treatment benefit with regard to described neurotransmitter system positively related bad spirit, nerve and physiological disorder.

Receptor in the brain is subjected to the negative adjusting that suppresses control loop of presynaptic usually.Therefore, for improving emotional pattern postsynaptic receptor (that is), desirably be that receptor before the relevant inhibitory synapse is reused agonist therapy with the receptor of bad spirit, nerve or physiological disorder negative correlation.Cause the downward modulation of this receptor at presynaptic inhibition receptor repetitive administration agonist, alleviate the nerve triggering (firing) that its depression effect also is increased in this raising emotional pattern postsynaptic receptor thus, and improve emotion.

Opposite strategy desirably is used for using the type postsynaptic receptor (that is, with the positively related receptor of bad spirit, nerve or physiological disorder) that represses one's emotion.For described receptor, desirably receptor before the relevant inhibitory synapse is used and repeat antagonist for treating.Repetition antagonist to presynaptic inhibition receptor is used the rise that causes this receptor, and the nerve of receptor triggers and the raising emotion after reducing its inhibitory reaction and alleviating the emotion inhibitory synapse thus.

Bad spirit, nerve or the physiological disorder that the bonded direct effect of part is relevant with this receptor type usually in during the very first time can initially worsen.For example, when the part of using was a antagonist with bad spirit, nerve or physiological disorder negative correlation, bonded short-term effect was the blocking-up receptor and prevents combining and triggering of receptor and natural neurotransmitter.Similarly, when the part of using was agonist with bad spirit, nerve or the positively related described acceptor type of physiological disorder, bonded short-term effect was to cause described part to trigger.Triggering can cause symptom to begin to worsen with the receptor of bad spirit, nerve or the positively related receptor of physiological disorder and inhibition and bad spirit, nerve or physiological disorder negative correlation.When the bonded short-term effect of ligand-receptor weakens (for example owing to remove part from described system) gradually, counter adaptation still provides the adjusting to the neurotransmitter system.Repetitive administration can cause to be strengthened gradually to the adjusting of neurotransmitter system.In embodiments more of the present invention hereinafter described, take measures to limit of the influence of the bonded direct effect of ligand-receptor to the patient.

Fig. 1 comprises that also emotion is with respect to the partial graph (b) of time under the situation about using with the suitable part of emotion associated receptor.Shown in the example of Fig. 1, interior emotion degenerated during the direct effect that part is used can be each very first time.This emotion changes is reduced to its steady state levels along with the bulk concentration of part and fades away.When ligand concentration comes back to its low steady-state level, counter adaptation still exist with use the second relevant time durations at every turn in and during the very first time after the overall improvement of emotion is provided.Fig. 2 uses the figure of the emotion of part with respect to the time in the method according to the invention.Shown in the emotion (i.e. the figure that tilts to raise in time generally) that improves constantly among Fig. 2, the intensity of counter adaptation increases in time, uses to cause other counter adaptive reaction at every turn.Thus, the treatment benefit of increase can be used repeating to be interrupted to use and realizing of part.Though Fig. 1 and 2 describes the net increase (net increase in mood) that counter adaptation wherein causes emotion, the technical staff will recognize that method as herein described can be used for treating the disease relevant with neurotransmitter of any number, and it is included in hereinafter in greater detail those.

At every turn using of part has the half life of using.Shown in the figure of Fig. 1 (a) part, the bulk concentration of part (for example ingestion of pills is used transdermal patch, or the intravenous beginning of using) when using beginning is in low relatively baseline values, is elevated to some maximum horizontal then.Reach after the maximum, the bulk concentration of part will reduce back baseline values (for example because metabolism/the secretion of part), and it keeps up to use next time at this.As shown in Figure 1, using half life is determined as the half-peak concentration that begins when bulk concentration is reduced to baseline values by its maximum horizontal from using.

Using half life will be the function of chemical compound half life (being the interior half life of body of ligand compound itself) and route of administration.For example, Fig. 3 be by injection chemical compound half life relatively the bulk concentration of the single administration of long part with respect to the figure of time.Because injection makes part very rapidly enter blood flow, use half life to approximate the chemical compound half life greatly.In the example of Fig. 4, the part of chemical compound half life much shorter (for example peptide) uses time-delay-release transdermal patch to use.At this, concentration is increased to the stable state Cmax more lentamente, and the consumption along with patch slowly reduces then.Remove in the situation of patch before exhausting, bulk concentration will be reduced to baseline values rapidly, as shown in Figure 5.Using half life can be and for example be less than an about week, is less than about three days, or is less than about one day.More desirably, using half life is less than about 16 hours; Be less than about 12 hours, be less than about 8 hours; Or be less than about 4 hours.In embodiments more of the present invention, specifically be to use those of relatively long part of chemical compound half life, the described half life of using, can be and is higher than about 4 hours; Be higher than about 12 hours; Be higher than about 16 hours; Or be higher than about 30 hours.

Described part has the chemical compound half life, and it is defined as half life in the body of part and active metabolite (promptly for the activated metabolite of the receptor of described acceptor type) thereof, because route of administration and breaking away from any effect.In some embodiments of the present invention, desirably use chemical compound relatively short chemical compound of half life.For example, in embodiments more of the present invention, described chemical compound half life, be less than an about week, is less than about 3 days, or is less than about 1 day.More desirably, described chemical compound half life, be less than about 16 hours; Be less than about 12 hours, be less than about 8 hours; Or be less than about 4 hours; Or be less than 1 hour.But some parts have relatively long chemical compound half life.For example, in embodiments more of the present invention, the chemical compound half life of part, be higher than about 4 hours; Be higher than about 12 hours; Be higher than about 16 hours; Or be higher than about 30 hours.

Keep the acceptable low and bonded direct effect of ligand-receptor that can tolerate simultaneously with the counter adaptation that maximizes part during desirably selecting to use.For example, but part use every day and carry out.In other embodiment, it during using 2 days or longer time; 3 days or longer time; 5 days or longer time; 1 week or longer time; 2 weeks or longer time; Or one month or longer time.Similarly, the part dosage of at every turn using is selected as being enough to excite the counter adaptive reaction, makes the bonded direct effect of ligand-receptor low and can tolerate for the patient but enough hang down.

When using the chemical compound half life to be higher than about 12 hours part, in order to strengthen counter adaptation, second part of the described acceptor type of repetitive administration desirably, the half life of at every turn using of using of described second part, be less than about 8 hours.In the example of the method according to this invention, with 24 hours administered compound half lifes half life of using be 24 hours part, used once in per 3 days, and use second part with 6 hours the half life of using every day.In described situation, if part is a receptor stimulating agent, described second part desirably is a receptor stimulating agent; If part is a receptor antagonist, described second part desirably is a receptor antagonist.

The interior bonded any direct effect of part was in level low and that can tolerate during ratio during using half life and using desirably was chosen as and makes the counter adaptation maximization keep the very first time simultaneously.According to one embodiment of the invention, the ratio during using half life and using is not higher than 1/2.Desirably, the ratio during using half life and using is not higher than 1/3.In embodiments more of the present invention, the ratio during using half life and using is not higher than 1/5; Be not higher than 1/8; Or be not higher than 1/12.Yet, desirably also may be to use part relatively frequently, to keep the counter adaptation of desired level.For example, in desirable embodiments more of the present invention, use half life and use between during ratio be higher than 1/100; Be higher than 1/50; Be higher than 1/24; Be higher than 1/12; Be higher than 1/8; Be higher than 1/5; Be higher than 1/4; Or be higher than 1/3.

The receptor of most described acceptor type with use the relevant very first time at every turn during in combine ideally with part, thereby cause the bonded counter adaptation of part.For example, the receptor of acceptor type at least about 30%, at least about 50%, at least about 75% or combine ideally with part in during each very first time at least about 90%.

Similarly, with use during the relevant very first time desirably long enough to produce substantial counter adaptation at every turn.For example, desirably for continuing, continue during each very first time, continue at least about 1 hour at least about 30 minutes at least about 5 minutes; Continue at least about 2 hours; Continue at least about 4 hours.In desirable embodiments more of the present invention, continue about 8 hours during each very first time.Yet, cause desirably will maintaining during the very first time and being no more than the required length of counter adaptation that obtains acceptable level in the obvious situation about worsening of bad disease in the bonded direct effect of part.For example, in embodiments more of the present invention, desirably continue during the very first time to be less than about 24 hours; Be less than about 16 hours persistent period; Be less than about 12 hours persistent period; Be less than about 8 hours persistent period; Or be less than about 6 hours persistent period.

In the desirable embodiment of the present invention, most of receptor with use at every turn relevant and during the very first time after second time durations keep not combining with part.The bonded low-level permission patient of ligand-receptor enjoys the effect (for example treating benefit) of counter adaptation and is not subjected to the influence of the bonded ill effect of any direct part.For example, desirably, be no more than approximately 50%, be no more than approximately 25%, be no more than about 10% receptor and in each second time durations, be incorporated into part.

Described with use at every turn the second relevant time durations be wherein most of described acceptor type receptor not with the bonded time of part.In each second time durations, described patient can enjoy any treatment benefit of counter adaptation, and this is owing to there is not direct ligand-receptor to continue in conjunction with effect.Thus, each second time durations is desirably long as far as possible.For example, each second time durations is desirably at least about persistent period of 2 hours; At least about 10 hours persistent period; Or at least about persistent period of 15 hours.Yet, desirably each second time durations can be kept shorter relatively, with shorten between using during, strengthen counter adaptation thus.For example, in embodiments more of the present invention, each second time durations desirably is no more than about 20 hours persistent period; Be no more than about 30 hours persistent period; Or be no more than about 15 hours persistent period.

In order to accumulate counter adaptation in time and to minimize any initial deterioration of described bad spirit, nerve or physiological disorder, desirably when using, bring into use the part of relative low dosage to treat at every turn, and increase dosage in time.The dosage that increases can be used for also explaining that the patient is to the cumulative toleration of part.For convenience, desirably intermittently increase in time dosage (promptly with during be longer than between using during mode increase dosage).For example, in embodiments more of the present invention, during between the following increase, increase described dosage: be no less than a week; Be no less than for 2 weeks; Be no less than for 3 weeks; Be no less than one month; Be no less than 2 months; Be no less than 3 months; Be no less than 6 months, or be no less than 1 year.When each dosage increases, described dosage desirably increase predose at least about 5%; At least about 10%; At least about 25%; At least about 50%; Or at least about 100%.Yet, desirably maximal dose can be remained in certain limit.For example, in embodiments more of the present invention, maximal dose can be in 300 times of predose, in 100 times of predose, and in 50 times of predose, or in 20 times of predose.

In an example of dosage, use ligand 1,2 or 3 weeks of low dosage.These predoses are enough high to induce the counter adaptive reaction, and are still enough low so that owing to the ligand receptor combination produces only MIN direct effect.Described subsequently dosage can increase.Described increase can be low to moderate 10%; But, desirably predose is doubled at least in order to induce the counter adaptive reaction quickly.4-6 is after week, and described dosage increases once more.Per 1,2,4 or 6 weeks of this pattern are carried out repetition.The terminal point of maximal dose will depend on individual toleration and the side effect of heavy dose and the appearance of direct effect to part.

In order to alleviate the bonded any direct effect of ligand-receptor, the time of desirably arranging part to use makes and appears at during the very first time in the time that the side effect to the patient is minimized.If the patient is in sleep state, then can not notice the bonded a lot of direct effects of ligand-receptor (for example, the decline of emotion).For example, when desirably arranging the time of application of part to make to come across the patient during most of very first time to fall asleep, thereby the bonded any direct effect of ligand-receptor can not noted.For example, at least 40%; At least 60%; Or when desirably appearing at the patient at least during 85% the very first time and fall asleep.In order to realize described arrangement of time, desirably carry out major part within hour before the patient goes to bed and use.For example, desirably at least 50%; At least 75%; At least 90% or at least 95% part carries out among being applied in patient hour before going to bed.

Using daytime does not have contradiction, and still, and in other embodiments of the present invention, carried out in the past patient hour before going to bed that at every turn is applied in of part.In the example of the method according to this invention, the patient is used described part every day, continues 2 or 3 months, occur counter adaptation and, for example, some relevant emotions are improved.If the patient wants special time by day to improve the emotion on daytime, fall into and use in the second relevant time durations thereby the time that part is used can change the desirable time.If the patient wishes that in the afternoon improve emotions at 6, can be in the afternoon 2 use the part that he suits (naloxone for example, the chemical compound half life is 1 hour μ and/or a delta opiate receptor antagonist).The direct effect of naloxone-receptors bind (unhealthy emotion) will continue only several hrs, to the 6 pm good emotion that causes of only remaining counter adaptation.

Using of part desirably repeats enough number of times to set up suitable big counter adaptation effect.Thus, in the method for the present invention, described using desirably carried out 5 minutes at least, and at least 10 minutes, at least 25 minutes or at least 50 minutes.

But part use at every turn oral administration, transdermal, by suck, in subcutaneous, intravenous, intramuscular, spinal cord, in the sheath, saturating mucosa or use osmotic pumps, microcapsule (microcapsule), implant or suspension carry out.Those skilled in the art can be based on the performance of part, and its chemical compound half life, required dosage and the required half life of using are selected route of administration.

The loading dose that the using of part desirably used fast Absorption (with realize quick ligand-receptor in conjunction with), and the dosage that absorbs gradually (so that required ligand-receptor keeps length during desirable very first time in conjunction with level).Have fast Absorption type jacket layer and can be used for described using than the rectal suppository at slow trapping type center.Alternatively, loading dose can be through sublingual administration, and the dosage of Xi Shouing can be via the patch transdermal administration gradually.

Carrier in the blood can be used for increasing using half life of part in the circulation.For example, United States Patent (USP) 6,610,825 and 6,602,981 (its full text content is incorporated this paper by reference into), part and hemocyte and protein binding have been described, prolong their method of using half life thus.(Curr MedChem, 9 (9) such as Adessi; May, 2002; 963-978) method of stabilized peptide part has been described.

Method of the present invention can be used for treating or disposing any bad disease relevant with the neurotransmitter system.The example of described disease comprises chronic pain (chronic pain), mood disorders (mood disorder), eating disorders (eating disorder), anxiety neurosis (anxiety disorders), motivation and performance problem (motivational and performance problems), inflammatory diseases, feels sick, vomiting, urinary incontinence, erythra, erythema or eruption, cardiovascular disorder, the disease relevant with immune system and the influence of aging.More examples of bad spirit, nerve or physiological disorder are described hereinafter.

Desirably also can be with antianxiety drug and ligand united using, to alleviate the bonded any direct effect of ligand-receptor.Antianxiety drug especially can be assisted and be alleviated ligand-receptor in conjunction with the influence to patient's sleep.Described antianxiety drug can for example influence the GABA approach.Described antianxiety drug can be for example benzodiazepine

The all diazepams of class (benzodiazepine) (diazepam), lorazepam (lorazepam), alprazolam (alprazolam), temazepam (temazepam), flurazepam (flurazepam) and chlordiazepoxide.Similarly, desirably with somnifacient or selectivity 5-hydroxy tryptamine reuptake inhibithors and ligand united using, to alleviate the bonded any direct effect of ligand-receptor.Each of these medicaments can be used simultaneously or in the different time with part.Desirably also tryptophan can be added in patient's the diet, as United States Patent (USP) 4,377,595 and 5,958,429 is described, and every piece of document is all incorporated this paper by reference in full into.

In some cases, the bonded minimizing that direct effect is the immune system function of ligand-receptor.Therefore, desirable is, can be during the very first time in autoimmune medicine and ligand united using.The example of suitable autoimmune treatment comprises medicine, as corticosteroid, chlorambucil, ciclosporin, cyclophosphamide, methotrexate, azathioprine, TNF alpha-2 antagonists, and treatment, as systemic enzyme treatment, gene therapy, radiotherapy.Certainly, recognize that other autoimmune medicine can be used for method of the present invention, comprise those of exploitation in the future as the technical staff.In some embodiments of the present invention, in second time durations, do not use the autoimmune treatment.

Similarly, desirable is, can be during the very first time in antiviral agent and ligand united using.The example of suitable antiviral agent comprises interferon, ribavirin, protease inhibitor, amantadine, rimantadine, pleconaril, antibody (monoclonal, anti--VAP, receptor resists-idiotype, external receptor and synthesis of receptor analogies), acycloguanosine, zidovudine (AZT), lamivudine, RNAase H inhibitor, integrase inhibitor, transcription factor is to the attached blocking-up thing of viral DNA, so-called ' antisense ' molecule, synthetic ribozyme, zanamivir and oseltamivir.Certainly, recognize that other antiviral drugs can be used for method of the present invention, comprise those of exploitation in the future as the technical staff.In some embodiments of the present invention, in second time durations, do not use antiviral agent.

Similarly, desirable is, can be during the very first time in antimicrobial, antifungal and/or antitumor agent and ligand united using.In some embodiments of the present invention, in second time durations, do not use antimicrobial, antifungal and/or antitumor agent.

Desirable is, can be during the very first time in anticarcinogen and ligand united using.Suitable anticarcinogen comprises; for example; amycin; busulfan; carboplatin; chlorambucil; cisplatin; cyclophosphamide; ifosfamide; chlormethine; melphalan; procarbazine; the temozolomide; daunorubicin; doxorubicin; idarubicin; bleomycin; mitomycin; mitoxantrone; plicamycin; cytosine arabinoside; fluorouracil; hydroxyurea; methotrexate; asparaginase; pegaspargase; irinotecan; hycamtin; bicalutamide; estramustine; flutamide; leuprorelin; megestrol; nilutamide; testosterone; triptorelin; Anastrozole; letrozole; aldesleukin; alemtuzumab; gemtuzumab; toremifene; trastuzumab; etoposide; Docetaxel; paclitaxel; vinblastine; vincristine; vinorelbine; altretamine; erlotinib (Erlotinib); gleevec; Rhizoma Curcumae Longae; tamoxifen; bortezomib (bortezomib); gefitinib (gefitinib); imatinib; be derived from 3; 4-methylene-dioxy-5,4 '-dimethoxy-3 '-the growth of cancer cells inhibitor of amino-Z-stilbene; his fourth and dibastic sodium phosphate prodrug thereof of oxybenzene; histone deacetylase inhibitors; octanedioyl aniline hydroxamic acid; Trichostatin A; sodium butyrate; metformin; five-lipoxidase (5-LO) antagonist; the antisense oligonucleotide of the RI α regulator subunit of targeting I type protein kinase A; vitamin E and analog thereof; tocopherol acid succinate (VES) and gene therapy.Certainly, recognize that other autoimmune medicine can be used for method of the present invention, comprise those of exploitation in the future as the technical staff.In some embodiments of the present invention, in second time durations, do not use antiviral agent.

Desirably can be with conventional medicine and ligand united using (for example simultaneously or use successively).When described medicament is a agonist by its number of counter adaptation and/or the already added acceptor type of sensitivity, or during the antagonist of the described acceptor type that has reduced by its number of counter adaptation and/or sensitivity, using of described medicament is especially desirable.Can comprise TCA, MAOI, SSRI, NRI, SNRI, CRF regulator, 5-hydroxy tryptamine presynaptic autoreceptor antagonist, 5HT with the example of the ligand united conventional dose of using ₁Agonist, dynorphin antagonist, GABA-A regulator, 5-hydroxy tryptamine 5H _2CAnd/or 5H _2BRegulator, β-3 adrenoceptor agonists, nmda antagonist, V1B antagonist, GPCR regulator or P substance antagonist.Desirably, other medicament has relatively short using half life, makes it to use in second time durations, and its effect disappears during to the using of part next time basically.Described application program keeps high-level counter adaptation, makes the effect of medicament in second time durations maximize simultaneously.

Desirable is also to utilize the direct combination of receptor that required clinical effectiveness is provided.For example part is the situation of receptor stimulating agent, desirably can one or more with use relevant and the very first time at every turn during after second time durations in use the antagonist of described acceptor type.Similarly, if described part is a receptor antagonist, desirably can one or more with use relevant and the very first time at every turn during after second time durations in use the agonist of described acceptor type.But, the agonist of described acceptor type desirably not with use the relevant very first time at every turn during in use.Half life,, less than 8 hours, or less than 6 hours, thereby it did not disturb using subsequently of agonist less than 12 hours in the body of preferred antagonist.

Ligand concentration (a part) and emotion are come illustration with respect to the figure of time (b part) in the body of another embodiment of the present invention by Fig. 6.In the method, counter adaptation is at first induced by the part of the patient being used the described acceptor type of one or more dosage.As shown in Figure 6, this can be undertaken by repetition or continuous administration high dose part.High relatively and part long-term dosage will be induced strong counter adaptation effect, but can cause the patient to be subjected to the influence of the bonded obvious direct effect of ligand-receptor, as the emotion of Fig. 6 with respect to shown in the figure of time.In described situation, desirably can in initially the inducing of counter adaptive reaction, keep the patient and be in hospital.After counter adaptive is reaction induced, repeat part is used the patient, use half life and use between during ratio be not more than 1/2.Can carry out repetitive administration substantially as mentioned above.

By regulating the function of neurotransmitter system, method of the present invention can be used for improving bad spirit, nerve and physiological disorder, even they can not cure the patient.Method of the present invention can make bad spirit, nerve and physiological disorder be obedient to (amenable) more for routine treatment.For example, if clinical depression is not cured, the emotion of using method of the present invention to cause is improved will help to improve depression.As mentioned above, the use of conventional antidepressant drug also makes it more effective.In another example, if cancer is not cured, its effect of the adjusting of neurotransmitter suppresses tumor growth and/or transfer, and can make conventional cancer therapy and/or immune system can remove the cancerous growths thing better.The treatment benefit that the adjusting of neurotransmitter causes for example can be, and the severity of the symptom relevant with sacred disease with spirit alleviates; Eliminate with spirit, nerve or physiological disorder related symptoms; Or cover and the related indication emotion raising of spirit, nerve or physiological disorder.

Method of the present invention can be in being used for the treatment of the patient bad spirit, nerve or physiological disorder.For example, method of the present invention can be used for treating bad spirit, nerve or physiological disorder such as mental state obstacle, eating disorders, pain obstacle, psychoactive substance abuse, anxiety disorder or the obsession that is pre-existing among the patient.Described method also can be used for alleviating any bad spirit, nerve or the physiological disorder that expection occurs in the future, for example owing to physical work in the future, and the physics wound, psychic trauma or medical procedure cause.Be described in more detail below many examples of the disease that can use method treatment of the present invention.

The P material system

According to one embodiment of the invention, the neurotransmitter system is P material (" SP ") system, and it comprises neurokinin P material, NKA and NKB as neurotransmitter.SP is a polypeptide, and known its mediators as the neurotransmitter and the pain sensation works.It is the tachykinin family member, and described family is that some row have similar C-terminal and different N-terminal and the different active polypeptide of SP sample.The SP receptor comprises NK-1, NK-2 and NK-3 receptor.SP is preferentially in conjunction with nk 1 receptor, and NKA is preferentially in conjunction with the NK-2 receptor, and NKB is preferentially in conjunction with the NK-3 receptor.

SP and receptor thereof are mainly seen in brain and the myeloid tissue.In spinal cord, the SP receptor sees the zone that is called dorsal horn, and it is the main site that pain signal is transmitted to brain.In brain, SP and receptor thereof see hypothalamus and corpus amygdaloideum with high concentration, the zone relevant with affective behavior, anxiety, stress and pain.In addition, SP also with nausea and vomiting, defense behavior, cardiovascular tonicity, salivation, inflammation, smooth muscle contraction and vasodilation and multiple mental sickness, such as schizophrenia (schizophrenia), manic depression (manic depressive psychosis), sexual dysfunction (sexualdysfunction), drug dependence (drug addiction), cognitive disorder (cognitive disorders), the dyskinesia (locomotive disorders) with depressed relevant.

If the neurotransmitter system is the SP system, acceptor type is the SP receptor, itself and a lot of bad spirit and nervous disorders positive correlation, and described part is the SP receptor stimulating agent.Counter adaptation causes the downward modulation of SP system, and is at least a in the following situation: SP, NKA and/or NKB are terminal or by the biosynthesis of pituitary gland or discharge and reduce at receptor; The decreased number of the binding site on receptor number and/or the receptor; Reduce with the bonded sensitivity of receptor and SP receptor stimulating agent and/or SP, NKA and/or NKB.

For example, the SP receptor stimulating agent can be based on peptide.In embodiments more of the present invention, the SP receptor stimulating agent is SP, NKA and/or NKB analog, or their pharmaceutically useful salt or derivant.For example, the SP receptor stimulating agent can be the P material; The P material of free acid form; Biotin-P material; [Cys ^3,6, Tyr ⁸, Pro ⁹]-P material; (disulphide bridges: 3-6), [Cys ^3,6, Tyr ⁸, Pro ¹⁰]-P material; (disulphide bridges: 3-6), [4-chloro-Phe ^7,8]-P material; [4-benzoyl-Phe ⁸]-P material; [succinyl group-Asp ⁶, N-Me-Phe ⁸]-P material (6-11) (Senktide); [Tyr ⁸]-P material; [Tyr ⁹]-P material; Shark P material peptide; GR73632[D-Ala-[L-Pro ⁹, Me-Leu ⁸] P material (7-11)]; [Sar ⁹, Met (O ₂) ¹¹] SP; GR73,632[δ-amino valeryl [Pro9, N-Me-Leu10]-P material (7-11)], [Glu (OBzl) 11] P material and hemokinin (hemokinin) 1 (HK-1) (homologue of P material); Or their pharmaceutically useful salt or carrier.

In another embodiment of the present invention, the SP receptor stimulating agent can be NKA or NKB analog, and it has C-terminal seven peptides that are similar to NKA (4-10) or NKB (4-10), or their pharmaceutically useful salt or carrier.For example, the SP receptor stimulating agent can be [Gln ⁴]-NKA, [Gln ⁴]-NKA (4-10), [Phe ⁷]-NKA, [Phe ⁷]-NKA (4-10), [Ile ⁷]-NKA, [Ile ⁷]-NKA (4-10), [Lys ⁵, MeLeu ⁹, Nle ¹⁰]-NKA (4-10), [Nle ¹⁰]-NKA (4-10), β-Ala ⁸]-NKA (4-10), [Ala ⁵]-NKA (4-10), ^*[Gln ⁴]-NKB, [Gln ⁴]-NKB (4-10), [Phe ⁷]-NKB, [Phe ⁷]-NKB (4-10), [Ile ⁷]-NKB,, [Ile ⁷]-NKB (4-10), [Lys ⁵, MeLeu ⁹, Nle ¹⁰]-NKB (4-10), [Nle ¹⁰]-NKB (4-10), β-Ala ⁸]-NKB (4-10), [Ala ⁵]-NKB (4-10), or their pharmaceutically useful salt or carrier.Similarly, the SP receptor stimulating agent can be [Arg]-NKB, Val wherein ⁷By alternate NKA of MePhe or NKB analog, or their pharmaceutically useful salt or carrier.

Other can be used for SP receptor stimulating agent of the present invention is SR48968, NK2 receptor antagonist ((S)-N-methyl-N[4-(4-acetylaminohydroxyphenylarsonic acid 4-[(Phenylpiperidine base subbase)-2-(3, the 4-Dichlorobenzene base)-and butyl] Benzoylamide]) and United States Patent (USP) 4,839,465; 4,472,305; 5,137,873; 4,638,046; 4,680,283; 5,166,136; 5,410,019; With 6,642, those that describe in 233, every piece of document is all incorporated this paper by reference in full into.

The predose of SP receptor stimulating agent (that is, the dosage of using for the first time) is desirably enough high inducing the counter adaptation effect, but not high to causing owing to the bonded direct effect that can not tolerate of ligand-receptor.For example, the predose of SP receptor stimulating agent can be about 0.5pmol/kg/min to about 20pmol/kg/min during the very first time in successive doses use.In desirable embodiments more of the present invention, the predose of SP receptor stimulating agent is 3pmol/kg/min-10pmol/kg/min, during the very first time in successive doses use.

The invention is not restricted to use SP receptor stimulating agent based on peptide.The SP receptor stimulating agent, comprise basically or all non--peptide SP receptor stimulating agent (for example, Chorev etc., Biopolymers, May 1991; 31 (6): those that describe 725-33), incorporate this paper by reference in full into) can be used in the method for the present invention.

The SP receptor stimulating agent can use any suitable route to use.Saturating mucosal administration (transmucosaladministration) is an especially desirable method of using the SP receptor stimulating agent.For example, use and can be sublingual administration or per rectum suppository.The dosage (so that keeping required level in the Len req of agonist-receptors bind during the very first time) that desirably uses the loading dose (to obtain the quick combination of SP receptor) of fast Absorption and absorb is gradually used the SP receptor stimulating agent.Rectal suppository with fast Absorption jacket layer and more slow trapping type center can be used for described using.Optional, loading dose can be through sublingual administration, and the dosage that absorbs gradually can be via the patch transdermal administration, and other approach comprises in spinal cord or uses in the sheath and is used for the treatment of pain.

Desirably, with use the relevant very first time at every turn during in do not use the SP receptor antagonist.In embodiments more of the present invention, yet the SP receptor antagonist is used in one or more second time durations.The limiting examples of SP receptor antagonist and the dosage of suggestion are as follows: SR 48968 ((S)-N-methyl-N-(4-acetylaminohydroxyphenylarsonic acid 4-Phenylpiperidine subbase)-2-(3, the 4-Dichlorobenzene base)-butyl] Benzoylamide); Osanetant and US 5,972,938; 6,576,638; 6,596,692; 6,509,014; 6,642,240; 6,841,551; 6,177,450; 6,518,295; US 6,369, and 074; AND US 6,586,432; With WO 95/16679; 95/18124; The chemical compound of describing in 95/23798.

Other SP (NK ₁) receptor antagonist comprises: L-760735 ([1-(5-{[(2R, 3S)-and 2-((1R)-1-[3, two (trifluoromethyl) phenyl of 5-] ethyl } the oxygen base)-3-(4-phenyl) morpholine-4-yl] methyl }-2H-1,2,3-triazole-4-yl)-N, N-dimethyl methylamine (dimethylmethanamine)]) (see Boyce, S waits Neuropharmacology.2001 Jul; 41 (1): 130-7); CP-96,345[(2S, 3S)-cis-2-(benzhydryl)-N-[(2-methoxyl group-phenyl)-methyl]-1-azabicyclic [2.2.2]-Xin-3-amine] (see Snider, etc., Science, 1991 Jan 25; 251 (4992): 435-7); SSR240600 ([(R)-2-(1-{2-[4-{2-[3, two (trifluoromethyl) phenyl of 5-] acetyl group }-2-(3, the 4-Dichlorobenzene base)-the 2-morpholinyl] and-the 4-piperidyl)-the 2-methyl propanamide] (see Steinberg, R. etc., Steinberg, R, Deng, JPharm Exper Ther, 303 (3), 1180-1188, December 2002, " SSR240600[(R)-2-(1-{2-[4-{2-[3,5-Bis (trifluoromethyl) phenyl] acetyl}-2-(3; 4-dichlorophenyl)-2-morpholinyl] ethyl}-4-piperidinyl)-2-methylpropanamide], a Centrally Active Nonpeptide Antagonist of the TachykininNeurokinin 1 Receptor): II.Neurochemical and Behavioral Characterization "); The NKP608[Cinchonic Acid [trans-(2R, 4S)-1-(3,5-couple-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidin-4-yl]-amine)] (see Spooren WP, etc., EurJ Pharmacol.2002 Jan 25; 435 (2-3): 161-70 and File, SE, Psychopharmacology (Berl) .2000 Sep; 152 (1): 105-9 is entitled as " NKP608, an NK1 receptor antagonists, has an anxiolytic action inthe social interaction test in rats. "); L-AT (N-acetyl group-L-tryptophan 3, the two benzyl esters of 5-) (see Crissman, A, Deng, Vol.302, Issue 2,606-611, August 2002, are entitled as " Effects ofAntidepressants in Rats Trained to Discriminate Centrally AdministeredIsoproterenol "); MK-869[Aprepitant] (see Varty, GB, Deng, Neuropsychopharmacology (2002) 27 371-379, " The Gerbil Elevated Plus-mazeII:Anxiolytic-like Effects of Selective Neurokinin NK1 Receptor Antagonists "); L-742,694[2 (S)-((3, two (trifluoromethyl) benzyls of 5-)-oxygen base)-3 (S) phenyl-4-((3-oxa--1,2,4-triazole-5-yl) methyl) morpholine] (see Varty, etc.); L-733060[(2S, 3S) 3-([3, two (trifluoromethyl) phenyl of 5-] methoxyl group)-2-Phenylpiperidine] (see Varty, etc.); CP-99,994[(+)-(2S, 3S)-3-(2-mehtoxybenzyl amino)-2-Phenylpiperidine] (see McLean, etc., J Pharm Exp Ther, Volume 267, Issue1, pp.472-479and Varty, etc.); CP-122,721[(+)-(2S, 3S)-3-(2-methoxyl group-5-trifluoromethoxy benzyl) amino-2-Phenylpiperidine] (see McLean, etc., J Pharm ExpTher, Volume 277, and Issue 2, pp.900-908and Varty, etc.); CP-96,345[(2S, 3S)-cis-2-(benzhydryl)-N-((2-methoxyphenyl)-methyl)-1-azabicyclic (2.2.2.)-octane-3-amine] (see Bang, etc., J Pharmacol Exp Ther.2003 Apr; 305 (1): 31-9); GSK 597599[Vestipitant]; GSK 679769 (seeing U.S. Patent Publications 20050186245 such as Hunter); GSK823296 (seeing U.S. Patent Publications 20050186245 such as Hunter); Saredutant (see VanSchoor, etc., Eur Respir J 1998; 12:17-23; Talnetant; Osanetant (is seen Kamali, F, Curr Opin Investig Drugs.2001 Jul; 2 (7): 950-6); SR-489686 (N-[4-[4-(acetylamino)-4-phenyl-piperidino]-2-(3,4-two chloro-phenyl) butyl]-the N-methyl-(S)-) Benzoylamide; SB-223412 (seeing U.S. Patent Publications 20050186245 such as Hunter); SB-235375 (3-hydroxyl-2-phenyl-N-[(1S)-the 1-phenylpropyl]-4-quinoline carbamyl), UK-226471 (seeing Hunter etc., U.S. Patent Publication 20050186245).

SP receptor antagonist suitable but non-limiting predose comprise about 12mg/kg/ hour/L-760735 that uses, lasting 8 hours (using) via iv; About 30ug/kg/ hour/CP-96 that uses, 345, continue 8 hours (using) via iv; The SSR240600 that about 0.1-10mg/kg/ uses (using) via ip or po; The NKP608 that about 0.01-0.1mg/kg/ uses (using) via po; The L-AT that about 1-10mg/kg/ uses; The MK-869 that about 0.01-3mg/kg/ uses; The L-742 of about 1-30mg/kg, 694; The L-733 that about 1-10mg/kg/ uses, 060; The CP-99 that about 3-30mg/kg/ uses, 994 or CP-122,721; And the saredutant (using) used of about 100mg/ via po.

SP neurotransmitter system and multiple bad spirit, nerve and physiological disorder positive correlation.The example of described disease comprises chronic pain (chronic pain), mood disorders (mood disorder), eating disorders (eating disorder), anxiety neurosis (anxiety disorder), motivation problem (motivational problems), psychoactive substance abuse (substance abuse disorder), inflammatory diseases, n or V (for example, cause by chemotherapy), urinary incontinence, erythra, erythema, eruption, fibromyalgia, the chronic fatigue syndrome, long-term back pain, chronic headache (chronic headach), long-term cancer pain, herpes zoster, reflex sympathetic dystrophy, neuropathy, inflammatory pain, the pain that expection occurs in the future (for example, because medical measure or physical exertion), major depression sexual disorders (major depressive disorders), wound retarded depression disease, temporary depressive emotion, manic depression (manic-depressive disorder), dysthymic disorder (dysthymic disorder), popularity mood disorders (generalized mood disorder), the sexual dysfunction of anhedonia (anhedonia) or non-organic, gluttony (overeating), obesity, apositia or polyphagia, generalized anxiety disorder state (generalized anxiety state), panic disorder (panicdisorder), phobia, obsession (obsessive-compulsive disorder), attention deficit companion hyperkinetic syndrome (attention deficit hyperactivity disorder), Tourette's syndrome, hysteric sleep disease (hysteria sleep disorder) or the relevant sleep disease (breathing-related sleepdisorder) of breathing, because study or memory problems motivation occurs and lack (a lack of motivation due tolearning or memory problems), psychoactive substance abuse is (such as anesthetis (narcotics), ethanol, nicotine, analeptic (stimulant), antianxiety drug, the CNS inhibitor, psychedelic drug and Fructus Cannabis), asthma, arthritis, rhinitis, conjunctivitis, inflammatory bowel, the inflammation of skin or mucosa, acute pancreatitis.The downward modulation of SP system has desirably produced the treatment benefit to bad spirit, nerve or physiological disorder.

The pain of nearly all type is except acute intense pain, all relevant with the SP system.SP is with to stab the original pain that causes irrelevant.Be dragged to afterwards the pain that just occurs owing to the SP approach causes.In similar mode, the pain of putting off a period of time behind the surgical operation is mediated by the SP approach.

Emotion mediates by the SP system.The increase of SP level sees the patient of clinical depression.Psychoactive substance abuse person's SP level increases, and in they, has depressed and/or irritated emotion generally time of Drug abuse not.Clinical depression raises relevant with the SP system with psychoactive substance abuse thus.In the mice that lacks the SP receptor, there is not the glad experience of morphine.Described mice is not to morphine addiction (Murtra, etc., Nature 405,180-183, May 11,2000).Because only opioid can not be induced gladly, Murtra research prompting SP system is the glad final approach that is mediated of opium.The fact that the SP antagonist can improve emotion rapidly is consistent with this discovery.Anxiety, stress, sexual dysfunction is relevant with emotion to a great extent with eating disorders and be subjected to the influence of SP system thus.

The SP system also with asthma (Kudlacz E.M., " Combined tachykinin receptorantagonists for the treatment of respiratory diseases ", Expert Opinion onInvestigational Drugs, Vol.7, No.7, July 1998, pp.1055-1062), the growth of nausea, cancerous tumour and shift (Palma, C, etc., Br.J.Cancer, 1999 Jan; Vol.79 (2): 236-43 and Friess, etc., Lab.Invest.2003 May; Vol.83 (5): 731-42) and urinary incontinence (AnderssonKE, Experimental Physiology, Vol.84 (1), 195-213) relevant.

The present invention uses the SP receptor stimulating agent to can be used for treating bad spirit, nerve or physiological disorder among the patient as the method for part.For example, the method for embodiment of the present invention can be used for treating any disease listed above.The method of embodiment of the present invention also can be used as the auxiliary treatment (for example slow down tumor growth and transfer) of cancer.

Method of the present invention also can be used with the SP agonist under such as migrainous situation in long-term recurrent pain situation.Similarly, because the SP system is raised in long-term pain syndrome,, they utilize the method for the present invention of SP agonist to treat so also can using.Described long-term pain syndrome comprises because the pain that nerve injury, long-term low back pain, reflex sympathetic dystrophy, cancer pain, herpes zoster and arthritis cause.

Method of the present invention can be used SP agonist prevent irritation before the incident relevant with pain.Can use method of the present invention to alleviate postoperative pain and the increase after-operation response to the anesthetis analgesic, it makes the anesthetis that can use low dosage obtain analgesic effect.Similarly, the SP agonist can be in described pain induction type competitive events such as football, is used for method of the present invention before hockey and the boxing.The SP agonist can use before any competition time is such as long-distance running with the impression that eases the pain, and it is inevitable for the use activity excessively for described muscle and lower limb.The pain reaction that alleviates finally allows the athlete himself to push higher degree to, causes achievement to be improved.

Method of the present invention also can use the SP agonist with treatment anxiety, stress, sexual dysfunction and eating disorders, and available SP agonist CAT scheme is improved.These diseases are relevant with emotion to a great extent, and therefore such as the improvement and overall emotion indirect correlation of these diseases, this is opposite with direct effect.

The also available SP agonist of method of the present invention is treated any or all addictive disorders.For example, method of the present invention can be used for treating psychoactive substance abuse, described medicine such as anesthetis, ethanol, nicotine/medicated cigarette, stimulus object, antianxiety drug, CNS inhibitor, psychedelic drug and Fructus Cannabis.In addition, the gambling and the brain of electronic game addiction be also similar to the psychoactive substance abuse problem unusually, also can use method of the present invention to treat.

Method of the present invention also can use the SP agonist to treat asthma by the severity that alleviates asthma attack.Can use the inhalation route of using to concentrate the counter adaptation effect in the lung (needing most counter adaptation) at this place.Method of the present invention also can use the SP agonist to alleviate any inflammatory reaction of multiple inflammatory diseases member, the inflammation of described inflammatory diseases such as arthritis, rhinitis, conjunctivitis, inflammatory bowel, skin or mucosa and acute pancreatitis.Method of the present invention also can use the SP agonist to treat nausea, those especially relevant with cancer chemotherapy nausea, and urinary incontinence.

Endogenous endorphins system

According to another embodiment of the present invention, the neurotransmitter system is an endogenous endorphins system, and it comprises the endorphins as neurotransmitter, and it is preferentially in conjunction with μ and/or delta opiate receptor.Endorphins is an endogenous opioid compound, and it works to the bonded influence of opiate receptor by them.The effect of μ and delta opiate receptor is consistent, and is subjected to the stimulation of opium and opioid compounds.M receptor is mainly regulated pain, but also regulates emotion.The δ receptor has opposite focus, mainly regulates emotion, but also regulates pain.

If neurotransmitter is an endogenous endorphins system, acceptor type is μ and/or delta opiate receptor, its common and bad spirit, nerve and physiological disorder negative correlation.Main relevant when mu opioid receptor is upset with low-level pain, main when delta opiate receptor is upset with glad relevant.Part is μ and/or delta opiate receptor antagonist, and counter adaptation causes the rise of endogenous endorphins system.Counter adaptation for example can be, and endorphins and/or biosynthesis by pituitary gland terminal at receptor or discharge increases; Endorphins binding site number on receptor and/or the receptor increases; The bonded sensitivity of receptor and μ and/or delta receptor agonist and/or endorphins increases; Or its any combination.

The method of embodiment of the present invention can use specificity μ receptor antagonist or specificity δ receptor antagonist to implement.For example, described method can use specificity μ receptor antagonist to implement, described antagonist such as clocinnamox mesylate, CTAP, CTOP, isothiocyanic acid etonitazene, β-funaltrexamine hydrochloride, two hydrochloric acid naloxonazines (naloxonazine dihydrochloride), Cyprodime, and their pharmaceutically useful salt, analog and derivant.Described method also can use specificity δ receptor antagonist to implement, described antagonist such as naltrindol (naltrindole), N-benzyl naltrindol HCl, maleic acid BNTX, BNTX, ICI-154,129, ICI-174,864 (N, N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH, wherein Aib is alpha-amido-isopropylformic acid .), naltribenmesylate, SDM25N HCl, 7-benzylidene naltrexone, and their pharmaceutically useful salt, analog and derivant.Those skilled in the art also can use non--specificity μ and/or opiate antagonist in the method for embodiment of the present invention, such as naloxone (naloxone) and naltrexone (natrexone).Non--restricted the representative example of non-specific opiate antagonist comprises nalorphine (Nalorphine), nalbuphine (nalbuphine), Lay Luo Fen (levallorphin), Cyc (cyclazocine), diprenorphine (diprenorphine).

Other μ and/or delta opiate receptor antagonist that can be used for method of the present invention comprises United States Patent (USP) 5,922,887; 4,518,711; 5,332,818; 6,790,854; 6,770,654; 6,696,457; 6,552,036; 6,514,975; 6,436,959; 6,306,876; 6,271,239; 6,262,104; 5,552,404; 5,574,159; 5,658,908; 5,681,830; 5,464,841; 5,631,263; 5,602.099; 5,411,965; 5,352,680; 5,332,818; 4,910,152; 4,816,586; 4,518,711; 5,872,097; 5,821,219; 5,326,751; 4,421,744; 4,464,358; 4,474,767; 4,476,117; 4,468,383; 6,825,205; 6,455,536; 6,740,659; 6,713,488; 6,838,580; 6,337,319; 5,965,701; 6,303,578; With 4,684,620 and International Patent Application WO/2004/026819 in describe those, every piece of document is all incorporated this paper by reference into.

In desirable embodiments more of the present invention, μ and/or delta opiate receptor antagonist are naloxone, naltrexone, nalmefene or nalbuphine, or their pharmaceutically useful salt or derivant.Naltrexone is ideal μ and/or δ receptor antagonist, but because its long chemical compound half life (48-72 hour) can not be used for all situations; And the half life of naltrexone itself is 9-10 hour, and the half life of its active metabolite (for example the bent alcohol of 6-β-Na (naltrexol) and 2-hydroxyl-3-methoxyl group are received bent pure) is much longer.Naloxone is especially desirable μ and/or the δ receptor antagonist that can be used in the embodiment of the present invention.About 1 hour of the half life of chemical compound of naloxone, but can not be Orally administered.Naloxone can be used or use by transdermal patch through intravenous, desirably can use time-delay-delivery formulations.Suitable transdermal patch is described in United States Patent (USP) 4,573,995, and it incorporates this paper in full by reference into.

Naloxone has 1-1.5 hour half life, and it is advantageously used in method of the present invention.Though 1-1.5 hour half life, enough be used to induce the counter adaptation reaction, is used for the half life that preferred part of the present invention will have 2-4 hour.In addition, naloxone has the oral administration biaavailability of non-constant, only is 5%, and this makes it be inconvenient to be used for the outpatient and uses.

Therefore in one aspect, the invention provides 3-hydroxyl morphinan and its derivant and prodrug the method for using as μ and/or δ opiate antagonist part, described μ and/or δ opiate antagonist part are oral biology available (orally bioavailable), and have and be longer than natural naloxone but be shorter than naltrexone or the half life of 8 hour half life of nalmefene.Preferred chemical compound had below 4 hours, and desirably was 2-4 hour half life.Randomly, can enter (transmucosal route) by saturating mucosa and give 3-hydroxyl morphinan as μ and/or δ opiate antagonist part.

Can increase the bioavailability of 3-hydroxyl morphinan chemical compound by using prodrug formulation.Be used for prodrug formulation of the present invention and comprise one or more chemical groups are attached to natural 3-hydroxyl morphinan chemical compound preventing the metabolic process (first pass metabolism process) that goes down to posterity first that it is the quick glucoside acidify (glucuronidation) of 3-OH part.It is nontoxic being used for attached chemical group of the present invention.In addition, attached chemical group is to remove in a period of time to make the total chemical compound half life of μ and/or δ opiate antagonist part keep less than those of 4 hours.

Described hereinly be used for 3-hydroxyl morphinan chemical compounds more of the present invention and have enhanced lipotropy.Bigger lipophile has strengthened strides the film absorption, and its effect is a bioavailability of improving oral and saturating mucosa.It further causes faster and transmission that pass blood brain barrier (blood-brain barrier) effectively.Improved like this transmission of passing blood brain barrier is preferred, because of it causes being reacted by the bigger counter adaptation of μ and/or delta opiate receptor antagonist.

In desirable embodiment of the present invention, because the naloxone analog has than the relative fact of short half life of other opiate antagonist (as naltrexone or nalmefene), μ and/or delta opiate receptor antagonist are the naloxone analog.

For to outpatient (or inpatient) counter adaptation therapeutic purposes, but be oral and/or saturating mucosa ground biological utilisation, desirably use a large amount of naloxone prodrug chemicals in order to make naloxone.These prodrugs are included in the modification of 3-OH part, 6-carbon, C-14 carbon and N-oxide prodrug formulation.The preferred modification is at 3-OH and/or 6-carbon potential point.

3-OH modifies

The morphine example:

Use the morphine analog how useful with modification and the such modification that explanation causes having more lipophilic structure.The morphine structure is:

When 3-OH and 6-OH group changed acetyl group into, chemical compound became diacetylmorphine, and it is called heroin in addition.Diacetylmorphine has favorable properties with respect to morphine and is that it has more lipotropy, so it is faster and be absorbed effectively and pass mucomembranous surface.For example, the oral administration biaavailability of morphine oral administration biaavailability @25-30% (Hasselstrom, J, etc., Clin Pharmacokinet.1993 Apr; 24 (4): 344-54 and Gourlay, GK, etc., Pain.1986 Jun; 25 (3): 297-312.), and the oral administration biaavailability of diacetylmorphine is @ 67% (Girardin, F, Deng, " Pharmacokinetics of highdoses ofintramuscular and oral heroin in narcotic addicts. " Clin Pharmacol Ther.2003Oct; 74 (4): 341-52.).In addition, the easier blood brain barrier that passes of diacetyl derivant.

For the naloxone chemical compound, when the 3-OH group changes 3-acetyl group naloxone derivant into, similar lipotropy appears.This enhanced lipotropy causes the obvious benefit with respect to natural naloxone chemical compound, comprises the acting duration of the improvement bioavailability of 3-acetyl group naloxone, enhanced effectiveness and increase.These benefits are by Linder and Fishman (" Narcotic Antagonists.1.... " JMedicinal Chemistry, 1973,16 (5): 553) explanation.

When carbochain further prolongs, when 3-OH being changed into 3-propiono, 3-bytyry, 3-caproyl, then lipotropy further increases.For example, with regard to 3,5 diester of morphine, the carbochain group that adds described growth causes similar or bigger effectiveness, together with longer acting duration, from increasing by 20% as many as, 5 double-lengths.[Owen, JA, etc., " Morphine Dieste rs.I... " Can J Physiol Pharmacol.1984Apr; 62 (4): 446-51 and " Morphine Diesters.II... " 452-456 page or leaf .]

Be used for 3-OH acetyl group that desirable chemical compound of the present invention comprises similar naloxone, bytyry, propiono, caproyl derivant with improve lipotropy (its effect is to strengthen the counter adaptation reaction), improve oral administration biaavailability, and the slight acting duration that increases the naloxone chemical compound.

The naltrexone example:

Naltrexone is similar to the naloxone structure, and only difference is the N part.Show among these differences figure below:

The naloxone naltrexone

Can modify the enhanced oral administration biaavailability that shows 3-hydroxyl morphinan by the 3-OH of analysis of compounds naltrexone.Particularly, the 3-OH of the naltrexone chemical compound of being made up of the similar thing ester of benzoate modifies and has shown enhanced bioavailability.For example, the acetylsalicylate of naltrexone and the bioavailability of o-aminobenzoa are in a ratio of 28 to 45 times with natural naltrexone chemical compound respectively (see Hussain, MA are etc., J Pharm Sci.1987 May; 76 (5): 356-8; Hussain MA, etc., Pharm Res.1988 Feb 5 (2): 113-5; US 4,668,685 and US 4,673,679).The metabolic by-product of these prodrugs of naltrexone is ortho-aminobenzoic acid and acetylsalicylate.Ortho-aminobenzoic acid is (normal-occurring) metabolic by-product of the normal presence of amino acid tryptophan.Aspirin is called aspirin more.Think that both of these by-products are safe and nontoxic with the required dosage of inducing counter adaptation.

Therefore, in desirable embodiment of the present invention, the naloxone chemical compound that such ortho-aminobenzoic acid aspirin 3-OH prodrug is modified is used for method as herein described.In addition; based on lipotropy and improved oral administration biaavailability in the increase of the attached thing of carbonyl in 3-OH site; in other desirable embodiment of the present invention, the naloxone chemical compound that alkanoyl (2-6 carbon atom) prodrug is modified is used for method as herein described.

Carbon-6 is modified

In desirable embodiments more of the present invention, use the naloxone derivant of modifying to carry out method as herein described at 6-carbon.Such modification relates to natural 6-=O chemical compound is converted into its 6-deoxidation, 6-methylene derivatives (6-=CH ₂), for example, as at US 3,814,768 and US 4,535, described in 157.

It is preferred that the 6-methylene is modified, because such transformation causes several benefits.These benefits comprise the effect of enhancing to opiate receptor, improve oral administration biaavailability and make molecular change must have more lipotropy.When the naltrexone molecule is carried out 6-=CH ₂During replacement, shown these benefits, described replacement produces the chemical compound that is called nalmefene.6-methylene naltrexone analog nalmefene has with respect to the improved character of naltrexone owing to several reasons, described reason comprises: 1) bigger bioavailability, 2) longer antagonist action persistent period, 3) with more competitive the combining of opiate receptor (opioid receptor) [it will produce bigger counter adaptation reaction], with 4) no dose dependent liver toxicity [Mason, BJ, etc., Arch Gen Psych1999, Aug; 56 (8): 719-24 and Dixon, R, etc., J Clin Pharm 1987; 27:233-239.].

Has 6-=CH ₂Another example of the improved receptor active that replaces shows by the 6-methylene derivatives of morphine.Such analog is that 75 times of effectiveness of parent morphine compounds (are seen Hahn and Fishman, J Med Chem.1975,18 (3): 259.).Hahn and Fishman point out that further 6-methylene naloxone derivant compares with natural naloxone chemical compound and have significantly more superior oral effectiveness.

Another such modification relates to and natural 6-=O chemical compound is converted into its 6-deoxidation (that is, 6-(H) ₂) analog.The 6-deoxidation is modified has several potential benefits with respect to the 6-=O group.At first, it makes chemical compound have more lipotropy.Secondly, it has increased the opiate receptor activity.For example, the 6-desoxymorphine has 10 times activity of natural morphine compounds.Similarly, 6-deoxidation naloxone has and compares enhanced antagonist activities with natural naloxone chemical compound and (see Table 1, Materials ﹠amp; Methods, Minakami, etc., Life Sciences 1962,10; 503-507.).The 3rd, it is intended to increase slightly the active persistent period,, increases half life that is.

Other such modification comprises and changes natural 6-=O chemical compound into 6-OH, 6-amine or 6-amide analogue.US 6,713, and 488 have described ' Neutral antagonist (neutral antagonist) ', wherein modify at the 6-carbon-based group.It is said that these chemical compounds are ' neutral ', because 6 carbon ketone groups are changed into-OH functional group, or amine, or amide etc.

Can all modify simultaneously at 3-OH and 6-C=O two sites.The two modification like this is intended to further strengthen oral administration biaavailability and counter adaptation reaction.For example, because ortho-aminobenzoic acid 3-OH replaces oral administration biaavailability 45 times have been strengthened, and also strengthened oral administration biaavailability because of the 6-C=O group being changed into 6-methylene or 6-deoxidation part, expected that therefore both make oral administration biaavailability strengthen more together at (3-OH and 6C modify).And, two transmission and enhancing opiate receptor activity that replacement is further used for improving passing blood brain barrier, the two all is used to strengthen the counter adaptation reaction, thereby improves clinical efficacy.

Other modification

The N-oxide derivative of 3-hydroxyl morphinan also can be used for method of the present invention.These derivants are at US 4,722, describe in 928 and 4,990,617.

The derivant that has the hydroxyl morphinan of replacement at 14-carbon also can be used for method of the present invention.US4,912,114 and US 4,272,540 (being incorporated herein this paper as a reference) the 3-hydroxyl morphinan chemical compound that has replacement at the 14-carbon-based group has been described.

Therefore, in some embodiments of the present invention, μ and/or delta opiate receptor antagonist are 3-morphinan chemical compound or its N-oxide or its pharmaceutically useful salt with following structure:

Wherein R is that R is pi-allyl, methacrylic, cyclopropyl methyl, dimethyl-allyl, tetrahydrofurfuryl (tetrahydrofurfuryl) or cyclobutylmethyl; R ¹Be H, (C ₁-C ₁₈Alkyl)-, (C ₁-C ₁₈Alkyl)-CO-, (C ₁-C ₁₈Alkyl) ₂N-CO-, (C ₁-C ₁₈Alkyl)-SO ₂-, (C ₁-C ₁₈Alkyl)-O-CO-, Ph-CO-, Ph-SO ₂-, Ph-NH-CO, wherein each Ph one or more substituent groups of randomly being independently selected from down group replace: (C ₁-C ₁₂Alkyl), (C ₁-C ₁₂Alkyl)-O-, Cl, F, Br, I, CF ₃, R ⁴O-and R ⁴ ₂N-, wherein each R ⁴Be independently selected from down group: H, (C ₁-C ₄Alkyl), H-CO-and (C ₁-C ₄Alkyl)-CO-; R ^2aAnd R ^2bBe selected from down independently of one another group: H, (C ₁-C ₆Alkyl), (C ₁-C ₆Alkyl)-O-, (C ₁-C ₆Alkyl)-CO-O-, R ⁵-O-, R ⁵ ₂N-, R ⁵-CO-NH-, R ⁵-S-and NO ₂, each R wherein ⁵Be independently selected from down group: H, (C ₁-C ₆Alkyl), (C ₃-C ₁₀Cycloalkyl), (C ₆-C ₁₀Aryl), (C ₁-C ₆Alkyl)-CO-, (C ₃-C ₁₀Cycloalkyl)-CO-, (C ₆-C ₁₀Aryl)-and CO-, wherein each randomly is selected from down 1-3 substituent group replacement of group: (C ₁-C ₁₂Alkyl), (C ₁-C ₁₂Alkyl)-O-, Cl, F, Br, I, CF ₃, R ⁴O-and R ⁴ ₂N-; Perhaps R ^2aAnd R ^2bForm O=or CH together ₂=; And R ³Be H, OH, CH ₃Or OCH ₃These chemical compounds are more specifically described in the U.S. Provisional Patent Application serial number 60/858,186 that is entitled as " OPIATE ANATOGONISTS FORCOUNTERADAPTATION THERAPY ", and this document is incorporated this paper by reference into.

Chemical compound with said structure can be desirable, because they can be prepared chemical compound half life to have 2-4 hour, and than the length of naloxone, but than the weak point of naltrexone.In addition, because in the blocking-up of the metabolic response of 3-OH, at replacement (that is R, of 3-OH ¹Be not the chemical compound of H) can give chemical compound the oral administration biaavailability bigger than naloxone.Therefore, these chemical compounds can be prepared with more convenient Orally administered form.R ¹Part is preferably nontoxic, this moment with it from 3-OH fracture alcohol, acid or amide to form its correspondence.Also these chemical compounds can be prepared having bigger lipotropy, it can strengthen strides film and absorbs, and this can improve the transmission that blood brain barrier is passed in oral and saturating mucosa bioavailability and increase.

The synthetic method of chemical compound that preparation has said structure can be obtained by methods known in the art by the technical staff, as in United States Patent (USP) 5,366,979; 6,713,488; 6,784,187; 4,912,114; 4,272,540; 4,322,426; 4,722,928; 4,990,617; 4,673,679; 4,668,685; 6,569,449; 4,535,157 and 5,908,846, and describe in the U.S. Provisional Patent Application that submit to, that be entitled as " ORALLYAVAILABLE NALOXONE DERIVATIVES AND METHODS OFSYNTHESIS " on June 15th, 2006 those, every piece of document is incorporated this paper thus by reference into.

In some embodiments of the present invention, R is a pi-allyl.R is the chemical compound half life that allylic chemical compound tends to have desirable weak point.

In some embodiments of the present invention, R ¹Not H.For example, R ¹Can be neighbour-amino benzoyl or neighbour-(acetoxyl group) benzoyl.R ¹Also can be (C ₁-C ₁₈Alkyl) or (C ₁-C ₁₈Alkyl) CO-.R ¹A desirable especially group be (C ¹-C ⁵Alkyl) CO-.As used herein, (C _n-C _mAlkyl) group is to have the straight chain of n-m carbon atom or the alkyl chain of branching.

In some embodiments of the present invention, R ^2aAnd R ^2bDo not form O=together.Such chemical compound is more lipophilic and has the opiate receptor activity bigger than naloxone chemical compound.For example, R ^2aAnd R ^2bThe H that can respectively do for oneself, or can form CH together ₂=.

In desirable especially embodiment more of the present invention, R ¹Not H and R ^2aAnd R ^2bDo not form O=together.Such chemical compound has the oral administration biaavailability and the blood brain barrier transmission of special increase.

In some embodiments of the present invention, R ³Not OH.

An example of suitable δ receptor-selective antagonist has following structure:

The predose of μ and/or delta opiate receptor is enough high to induce the counter adaptation effect, does not still have high to causing the patient direct effect that can not tolerate to occur.For example, the predose of μ and/or delta opiate receptor antagonist can be equal to about 2mg/ and is applied to the naloxone that about 200mg/ uses.In desirable embodiments more of the present invention, the predose of μ and/or delta opiate receptor antagonist is equal to about 10mg/ and is applied to the naloxone that about 100mg/ uses.

If use naloxone as μ and/or delta opiate receptor antagonist, predose can be 5-500mg/ and uses.Desirably, described predose is that 10-50mg/ uses.In embodiments more of the present invention, each dosage of naloxone is higher than 10mg/ and uses; Being higher than 10.5mg/ uses; Being higher than 11mg/ uses; Or be higher than 15mg/ and use.Desirably, the predose of naloxone is at least about 30mg/ and uses (in during 8 hours), because this amount causes the blocking-up fully of opiate receptor.Desirably, the maximal dose of naloxone is not higher than 3000mg/ and uses.

In an example of naloxone daily dose scheme, the predose of naloxone is used for 30mg/ in during 8 hours.After 2 weeks, dosage is doubled.After two weeks, described dosage is increased to 120-160mg/ and uses.After one month, described dosage was increased to 300mg/ and uses, and was increased to 500-600mg/ after two weeks and used.After two weeks, described dosage is increased to 1000mg/ and uses, and is increased to 1500-2000mg/ after two weeks and uses.Alternatively, can use much higher predose (for example, 100-500mg/ uses) more promptly to accumulate counter adaptation.The naltrexone of low dosage (for example, 10-25mg/ uses) can use to realize extra counter adaptation effect with naloxone.

In the example of the dosage of naltrexone, naltrexone is used with the predose of 10-25mg every day.Optional, bigger dosage (for example, 25-200mg/ uses) can use weekly once, twice or three times.For heavy dose of naltrexone, longer relatively during the very first time, and in some cases can be overlapping with patient's recovery time.

μ and/or delta opiate receptor antagonist can be oral, transdermal, through spinal cord, in sheath, via suck, through subcutaneous, through intravenous, intramuscular or saturating mucosa, or use via osmotic pumps, microcapsule, implant or suspension.In some embodiments of the present invention (for example, under the chemical compound relative short situation of half life of μ and/or delta opiate receptor antagonist), desirably use, or transdermal (for example using patch) is used to provide length enough using half life with the form of time-delay-release or slow-delivery formulations.Use if μ and/or delta opiate receptor antagonist are the forms of transdermal administration or with time-delay-release or slowly-delivery formulations, it was discharged in 2-12 hour duration.For half life in the high body that the part in the short time is provided, desirably use the fast Absorption loading dose to use using of μ and/or delta opiate receptor antagonist.For high bulk concentration and desirably long the using half life that part is provided fast, desirably use loading dose and transdermal administration or the time-delay-release or the slow delivery formulations of fast Absorption.The transdermal patch of naloxone, naltrexone and nalbuphine is described in United States Patent (USP) 4,573, and in 995, it incorporates this paper in full by reference into.The present invention further comprises the route of administration of using oral and saturating mucosa opiate antagonist simultaneously.Its reason is that mucosal administration is intended to cause the high cyclical level of quite instant opiate antagonist chemical compound.When using a kind of aforesaid prodrug, such using also can cause the high level at once of intracranial opiate antagonist.When purpose is that quick so high-caliber opiate antagonist is important when inducing best counter adaptation reaction.

Another aspect of the present invention relates to following option: the oral dose of opiate antagonist can be used with saturating mucosa dosage.Yet saturating mucosal administration causes continuing the Rapid Cycle level of short time, oral administration of compound has the cyclical level of onset gradually, thereby this administration form is intended in circulation the high relatively cyclical level of opiate antagonist chemical compound is kept the longer time, that is, and and as many as 8 hours.For example, modify if use natural naloxone molecule or 3-OH acetyl group by saturating mucosal route, effect will only continue 2-4 hour in circulation so, its come down to these chemical compounds the result of half life (1-1.5 hour).Because if the opiate antagonist effect is prolonged more, that is, 8 hours (time of sleep cost) of as many as, counter adaptation can be maximized, and oral naloxone analog will cause the time that prolongs more of the high cyclical level of naloxone.In other words, the dosage that gives by saturating mucosal route is intended to produce the Rapid Cycle level that continues the short period, and oral dose was kept as many as 8 hours with cyclical level.

Another aspect of the present invention relates to uses different route of administration.For example, can select to come begin treatment with a kind of in the aforesaid 3-hydroxyl morphinan chemical compound by saturating mucosal administration approach.This carries out to reduce acute side effects than low dosage with described chemical compound.Can be switched to Orally administered, wherein bigger dosage after a period of time will be practical more, and adapt to side reaction at this moment individual cognition.

In embodiments more of the present invention, desirably use specificity μ and/or δ receptor antagonist and non--specificity μ and/or delta opiate receptor antagonist.Two types antagonist also can be used basically simultaneously or sequentially.The counter adaptation effect of Yan Gengda is desirably used non--specific antagonists at described method commitment because non--specific antagonists provides usually than specificity μ or δ opiate antagonist.

Because body antagonism opium medicine (anti-opiate) produces drug resistance after using about 8 days for the first time, desirably increase the dosage of μ and/or delta opiate receptor antagonist in time.For example, increase dosage in desirably during a week to two weeks.

Desirably, the endorphins receptor stimulating agent not with use the relevant very first time at every turn during in use.In embodiments more of the present invention, yet the endorphins receptor stimulating agent is used in one or more second time durations.Endorphins agonist suitable but limiting examples comprises opiates such as morphine, codeine, hydrocodone, fentanyl and oxycodone.Morphine can dosage 1-20-50mg i.v. or was continued in 1-50mg/ hour to discharge, use via any proper method (such as transdermal, intravenous injection (i.v.), SQ, IM or pump); Fentanyl can dosage 0.1-0.5mg, discharge gradually in 8 hours via any suitable means, and described suitable means are such as transdermal, SQ, IM or pump; Codeine can be used by dosage 10-100mg p.o. in every 4-6 hour; Hydrocodone can be used by dosage 5-25mg p.o. in every 4-6 hour; Oxycodone can dosage 5-100mg p.o. be used in 4-8 hour such as slow release transdermal, i.m. or SQ by any suitable means in per 4 hours).

The aminoacid sequence of enkephalin is any active analogue thereof of H-Tyr-Gly-Gly-Phe-Met-OH or H-Tyr-Gly-Gly-PheLeu-OH or these aminoacid sequences with pharmaceutically useful carrier.Enkephalin can dosage 1.0 μ g/hr discharges (transdermal, i.v., SQ, i.p.i.m. infusion pump) continuously and uses.

β endorphins (31 amino acid whose peptides) or any and all active analogue thereof, for example, beta-endorphin-(1-26), [D-Ala2] beta-endorphin or [Leu5] beta-endorphin and pharmaceutically suitable carrier are used.The β endorphins can discharge (for example transdermal, i.v., SQ, i.p.i.m. infusion pump) by dosage 1.0 μ g/hr continuously.

μ selective agonist such as carfentanil can be used by dosage 1-25 μ g/kg; [D-Ala2, NMe-Phe4, Gly-ol5] enkephalin and any active analogue thereof with pharmaceutically suitable carrier.The dosage 1.0 μ g/hr that enkephalin can be advised discharge (for example i.v., i.m., SQ, pump or transdermal) continuously and use.

δ selective agonist such as DPDPE ([D-Pen2, D-Pen5] enkephalin); SB-235863; And SNC80.The dosage 1.0-5.0 μ g/hr that DPDPE can advise discharges (for example, i.v., i.m., SQ, pump or transdermal) continuously and uses.SB-235863, ([8R-(4bS ^*, 8a α, 8a β, 12b β)] 7,10-dimethyl-1-methoxyl group-11-(2-methyl-propyl) oxygen base carbonyl 5,6,7,8,12,12b-six hydrogen-(9H)-4,8-methylene benzo furo [3,2-e] pyrrolo-[2,3-g] isoquinolin hydrochloride) can use by dosage 70mg/kgp.o.See PaolaPetrillo, wait J.Pharmacology and Experimental Therapeutics, first published onOctober9,2003; DOI:10.1124/jpet.103.055590.SNC 80 can dosage 50-75mg/kg slowly release, transdermal, i.p., SQ, pump in a few hours, etc.) use.See EJ Bilsky, etc., Pharmacology and Experimental Therapeutics, Volume 273, and Issue 1, pp.359-366,04/01/1995.

Desirable is to use the CRF receptor antagonist in second time durations.Appropriate C RF receptor antagonist comprises R121919, DMP696, antalarmin, CP-154,526, SSR125543A, 2-arylamino-4-trifluoromethyl-amino methyl thiazole antagonist, astressin, alpha-helix CRF chemical compound, and United States Patent (USP) 5,132,111; 5,278,146; 5,824,771; 5,844,074; 6,214,797; 6,670,371; The chemical compound of describing in 6,812,210 and 6,953,838 (every piece of document is incorporated this paper thus by reference into) and their pharmaceutically useful salt, analog and derivant.The CRF system is more specifically described below.

Desirable is, CRF agonist and μ and/or delta opiate receptor antagonist is co-administered, and at every turn using of CRF receptor stimulating agent has the half life of using, wherein use half life and use between during ratio be not more than 1/2.Appropriate C RF receptor stimulating agent comprises the analog of corticotropin-releasing factor, with and pharmaceutically useful salt and derivant.

When using CRF receptor stimulating agent and/or AVP receptor stimulating agent in conventional dosage regimen, desirable is, but repetitive administration μ and/or delta opiate receptor antagonist are as described herein.Because the following fact this can be desirable: use CRF receptor stimulating agent and/or AVP receptor stimulating agent can have following uninsured consequences: the β endorphins of anterior pituitary (anterior pituitary gland) is discharged downward modulation.The endorphins of such reduction discharges will induce about improving the required opposite effect of unacceptable disease, described unacceptable disease (as depression and anxiety disorder) and the horizontal reverse correlation of circulation endorphins.The repetitive administration opiate antagonist can have two kinds of important effects: blocking-up is by the downward modulation of the endorphins of CRF receptor stimulating agent and/or AVP receptor stimulating agent, causes the rise of aforesaid endorphins system in addition.Therefore, in some embodiments of the present invention, in second time durations relevant, use CRF receptor stimulating agent and/or AVP receptor stimulating agent with use μ and/or delta opiate receptor antagonist at every turn.

Endogenous endorphins system and μ thereof and/or delta opiate receptor and multiple bad spirit, nerve and physiological disorder negative correlation.The example of described disease comprises pain, mood disorders, eating disorders, anxiety neurosis, motivation problem (motivational problems), psychoactive substance abuse, motivation or performance are not enough, the immune system relevant disease, the wound that needs healing, the pain that expection occurs in the future (for example, because operation in the future or because physical exertion in the future), chronic pain syndrome, acute pain, fibromyalgia, the chronic fatigue syndrome, long-term back pain, chronic headache, herpes zoster, reflex sympathetic dystrophy, neuropathy, inflammatory pain, long-term cancer pain, major depression sexual disorders, wound retarded depression disease, temporary depressive emotion, manic depression, dysthymic disorder, the popularity mood disorders, the sexual dysfunction of anhedonia or non-organic, gluttony, obesity, apositia or polyphagia, the generalized anxiety disorder state, panic disorder, Tourette's syndrome, hysteric sleep disease or the relevant sleep disease of breathing, because appearring in study or memory problems, motivation lacks, psychoactive substance abuse is (such as anesthetis, ethanol, nicotine, analeptic, antianxiety drug, the CNS inhibitor, psychedelic drug and Fructus Cannabis), the desirable spirit or the motivation of physical exertion or prepare not enough (physical training for example, sports, study or test), immune correlated disease is such as infection, AIDS or cancer, and the wound that needs healing.The rise of endogenous endorphins system has desirably produced the treatment benefit to bad spirit, nerve or physiological disorder.

Endogenous endorphins system is relevant with pain, and this is because endorphins can synthesize thereby reduce pain inductive substance SP in conjunction with the opiate receptor of mediated pain.Endogenous endorphins system also with stress (United States Patent (USP) 5,922,361 and 5,175,144), wound healing (Vinogradov VA, Spevak SE, etc., Biand U.S.Patent 5,395,398), psychoactive substance abuse, eating disorders (Full ﹠amp; Fulfilled:thescience of eating to your soul ' ssatisfaction, by Nan Allison; Carol Beck, Publisher:Nashville, TN:A ﹠amp; B Books,

1998, ISBN:0965911799), the motivation problem (Tejedor-Real, P is etc., Eur J Pharmacol.1998 Jul 31; 354 (1): 1-7); Immunoreation (Wybran, Fed Proc.1985 Jan; 44 (1Pt1): 92-4 and United States Patent (USP) 5,817,628) and cancer (Zagon, IS, etc., Cancer Lett, 1997; 112:167-175; United States Patent (USP) 6,737,397; 6,136,780; With 4,801,614) relevant.

Endogenous endorphins system is also relevant with emotion.Glad is the most tangible emotion effect of opium, and it makes people's good and happy sensation improve.The glad adjusting that is subjected to the endogenous endorphins.Endorphins discharges with happy experience, such as the thing of feed, motion, triumph, romance.Think that the release of endorphins produces good mood as " award ", its as incentive mechanism so that individuality is full of nutrition and reproduction needs.Endogenous endorphins system is an anxiety reduction to other function of emotion, especially with regard to stress.Rang H.P (1995) .Peptides as Mediators.In H.P Rang ﹠amp; M.M.Dale, Pharmacology, Churchill Livingstone, New York.) confirmed that endorphins discharges in emotional stress, it plays induces glad emotion with anxiety reduction.

Endogenous endorphins and synthetic opium all can be induced glad.Difference is that the endogenous endorphins degrades rapidly their synapse and acceptor site, makes that effect is a short-term.Because short-term effect can not produce toleration or dependency.Synthetic opioid, such as anesthetics, its response time is longer.Therefore, they are relevant with dependent generation.Do not develop and have strong analgesic effect and have very little or do not produce dependent possible synthetic opioid.Because the endogenous endorphins has the glad inducibility similar to opioid, preferably uses the endogenous endorphins to induce the emotion of improvement.Yet because the using of synthetic endorphins of the dosage of relatively large and time lengthening can be relevant with dependent development with toleration, they are not desirable long-term treatment medicaments.

μ is relevant with emotion to a certain extent with delta opiate receptor.The impression of the main mediated pain of μ receptor, but these receptors and endorphins/also induce glad when the opium chemical compound combines.δ receptor unclear in regulating pain, but they probably with glad get in touch more tight.Delta receptor agonist shows antidepressant activity in rat in forced swimming test.In addition, the evidence from zooscopy shows that δ-opioid recdptor participates in locomotor activity (motivational activity).Behavior by glad control during their preferred participate in.Broom waits (Jpn J.Pharmacol.2002 Sep; 90 (1): 1-6) confirm that delta opiate receptor plays an important role in depression.

The present invention uses μ and/or δ receptor antagonist to can be used for treating bad spirit, nerve or physiological disorder among the patient as the method for part.For example, method of the present invention also can be used for treating any disease in the above-mentioned disease.Method also can be used as the auxiliary treatment of cancer according to embodiments of the present invention.

The present invention uses the method for μ and/or δ receptor antagonist to can be used for treating the pain that expection occurs in the future.For example, the patient is arranged to carry out elective surgery, and for example within one month, method of the present invention can be used μ and/or delta opiate receptor, adopts time durations before high night, the dosage art was intervened.After the operation, the patient can have enhanced reaction to pain because endogenous endorphins system raises.In addition, because the sensitivity of μ and/or delta opiate receptor strengthens, the accumulated dose of the anesthesia pain medication of needs of patients reduces.Described method is interrupted after may being preferably in operation at once, thereby postoperative pain can not increase owing to the direct effect of receptor antagonism.It begins after can be about a couple of days once more, in case pain relief, thus the counter adaptive reaction kept.

In the example according to aftertreatment of the present invention, 49 years old male is arranged at and accepts the knee reconstruction operations in 6 weeks.He begins to treat with naloxone patch 200mg earlier, and it is mixed with fast Absorption in 6-8 hour as mentioned above, based on night.In order to alleviate the inductive anxiety of this medicament, this male is used antianxiety drug diazepam (1-5mg) and naloxone patch at night.After this dosage continued for 2 weeks, the naloxone at night is increased to 400mg.Can use antianxiety drug as needs.After 2 weeks, the dosage at night of naloxone is increased to 600-800mg.Performed the operation that night, and several evenings of peri-operation period, naloxone do not given.Only give patient's standard postoperative analgesia medicine, such as morphine and codeine.The dosage of these materials is compared greatly with the individuality of experience the type operation and is reduced, and this is because this patient's endorphins system is raised.In the optional method, after first 2 week of naloxone treatment, give the naloxone that same patient specificity μ receptor antagonist and dosage increase, to strengthen the rise of regulating pain type μ receptor.

Method of the present invention can use μ and/or delta antagonist to improve patient's emotion in the treatment of depressed and relevant disease.At first, can use non--specificity opiate receptor antagonist (for example, naloxone) and induce the counter adaptive reaction.In the treatment afterwards, desirably use the specificity delta opiate receptor antagonist, this is because delta opiate receptor is relevant strongly with emotion.Certainly can use mu opioid receptor antagonists, especially when long-term pain is relevant with depressive emotion.When treating depressed patient, those skilled in the art will monitor closely because any acute emotion that antagonist-receptors bind causes worsens the ill effect to the patient that causes.

Use in the example of method of method of the present invention treatment depressive patient, it is relatively poor and side effect arranged to the reaction of using conventional antidepressant drug to be diagnosed as the 35 years old male who suffers from clinical depression.His special consultation the interim probability that worsens of depressive state, comprise suicidal tendency.Hospitalization or suitable mental hospital are considered when the higher patient's of suicide probability treatment begins.After described measure onset, he brings into use non-specific opiate antagonist naloxone to carry out counter adaptation therapy scheme.The beginning before sleep of saturating mucosa naloxone preparation, loading dose 20mg.The saturating mucosa dosage of 30mg is made among 6 hours and absorbs, and uses simultaneously.The per 8 hours dosage of this 50mg used for 2 weeks.In second week, saturating mucosa dosage is increased to 50mg.Transdermal dosage compositions was 50mg in 6 hours, total amount 100mg.This dosage was used 1 month.Now, back 6 months of treatment beginning, loading dose is saturating mucosa of 100mg and a 100mg transdermal among 6 hours.Other 4-6 is after week, and loading dose is increased to 250mg, and 6 hours accumulated doses are 500mg.After other 1-2 month, loading dose is increased to 500mg, and 6 hours total amount subsequently is 500mg.1 or 2 or 3 months after, be increased to 6 hours transdermal dosage compositions of loading dose and the 1000mg of 1000mg.Maximum is in the sustainable long time of this 2000mg accumulated dose.Or it can continue to be increased to 2,500 subsequently 1 year or longer time, or 3,000 or 4,000mg.Maximal dose in case good clinical response appears or in case side effect is excessive or if the liver function enzyme raises to blood testing situation under arrive platform.The persistent period of maximum tolerable dose administered over prolonged is used to keep treatment.If treatment is ended, carefully monitor any sign of patient's mood disorders recurrence.

Above-mentioned patient's selection is to add delta opiate receptor antagonist after 6 week to 3 of treatment month, and naloxone.The sustainable increase of naloxone dosage or it can reduce earlier gradually when with the delta antagonist coupling.Non--the peptide delta opiate receptor antagonist, can be used such as one of naltrindol, natriben or medicament discussed above.The peptide delta antagonist, such as ICI-154,129 or ICI-174,864 peptides also can use.The predose of naltrindol is higher than the predose of naloxone.It may be up to 10mg/kg/ and uses.Naltrindol can be used as the transdermal chemical compound or uses any other effective preparation to use.

For the possible patient who suffers from severe depression that commits suiside was arranged, if predose is big especially, main consideration was the dosage arrangement.In the desirable embodiment of the present invention, suffer from the people of clinical depression since exist to commit suiside may, should do not treated or hospitalization or in suitable mechanism's treatment to monitor the patient better.These patients' dosage is relatively low in the treatment beginning, and increases dosage with slower speed.Therefore, the treatment for the patient of depression only needs the 10mg naloxone of loading in the time of may beginning, in subsequently 6 hours 10 or 20mg will be absorbed, total predose is 30mg.Similarly, the dosage after 2 weeks increases that to compare degree more gradual with top example.When 2 weeks, use 20-40mg as load doses and in subsequently 6 hours with using 20mg.This increase gradually continues a lot of months, and this is to obtain maximum clinical to react required.

The dynorphin system

According to another embodiment of the present invention, the neurotransmitter system is the dynorphin system, and it comprises that dynorphin is as neurotransmitter.Dynorphin is the endorphins type of compounds, and it is preferentially in conjunction with kappa receptor.Dynorphin is opposite with the endorphins effect usually; Its with combination of kappa receptor usually and emotion degenerate relevant.

If the neurotransmitter system is the dynorphin system, acceptor type is a kappa receptor, its common and bad spirit, nerve and physiological disorder positive correlation.Kappa receptor is mainly relevant with agitation when irriate.Part is the kappa receptor agonist, and counter adaptation causes the downward modulation of dynorphin system.Counter adaptation for example can be, and the biosynthesis of the dynorphin of receptor end and/or pituitary gland or release reduce; The decreased number of the dynorphin binding site on receptor and/or the receptor; The bonded sensitivity of receptor and μ and/or delta receptor agonist and/or dynorphin reduces; Or its any combination.Counter adaptation also can raise D2 (dopamine) receptor, itself and depressed negative correlation.

Multiple K receptor stimulating agent can be used among the present invention.For example, the kappa receptor agonist can be the agonist based on peptide, such as dynorphin [dynorphin [A1-17], H-TYR-GLY-GLY-PHE-LEU-ARG-ARG-ILE8-ARG-PRO-LYS-LEU-LYS-T RP-ASP-ASN-GLN-OH], with and all bioactive peptide fragments and analog with and pharmaceutically useful salt or carrier.For example, the kappa receptor agonist can be the active C-terminal fragment of dynorphin A (1-8), or its pharmaceutically useful salt or carrier.

Non--peptide type that the kappa receptor agonist also can be.For example, the kappa receptor agonist can be non-benzmorphan (non-benzomorphan); Enadoline; PD117302; CAM569; PD123497; GR 89,696; U69,593; TRK-820; Trans-3,4-two chloro-N-methyl-N-[1-(1-pyrrolidinyl) cyclohexyl] benzene-acetamide; Asimadoline (EMD-61753); Phenyl acetamide; Tetrahydro-1,4-thiazine; Piperidines; Benzo [b] thiophene-4-acetamide; Trans-(+/-)-(PD-117302); 4-benzofuran acetamide (PD-129190); 2,6-methylene-3-benzene Zha Zuoxin-8-alcohol (MR-1268); Morphinan-3-alcohol (KT-90); GR-45809; 1-piperazine carboxylic acid (GR-89696); GR-103545; Piperazine; GR-94839; Xorphanol; Phenyl acetamide (RU-49679); Fedotozine; Phenyl acetamide (DuP-747); HN-11608; Apadoline (RP-60180); The spiradoline mesylate; Phenyl acetamide is trans-the U-50488 metilsulfate; 3FLB; FE200665; FE200666; The analog of MPCB-GRRI or MPCB-RRI, benzo morphenol (benzomorphan) κ opiates, such as bremazocine (bremazocine) and ethyl ketone cyclazocine (ethylketocyclazocine), or their pharmaceutically useful salt or carrier.

The kappa receptor agonist can be U50,488 (trans 3,4-two chloro-N-[2-(1-pyrrolidinyl) cyclohexyl] phenyl acetamide); Spiradoline (U62,066E); Enadoline [(5R)-5 α, 7 α, 8 β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro [4,5] naphthalene-8-yl]-4-benzofuran acetamide mono-hydrochloric salts] or PD117302[(±)-trans-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzo [b] thiophene-4-acetamide mono-hydrochloric salts] and separately (+)-isomer (CAM569 and PD123497) (Parke-Davis Research Unit, Cambridge, UK), they every kind all be high selectivity arylacetamide κ opioid; GR89,696 (4-[(3, the 4-Dichlorobenzene base) acetyl group]-3-(1-pyrrolidinyl methyl)-1-piperazine carboxylic acid mesaconic acid ester (piperazine carboxylic acid methyl ester fumarate)), from U50, the structural development of 488H and the prototype arylacetamide that comes, it is the same with the K1 agonist to have efficient; U69,593[(5 α, 7 α, 8 β)-(+)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro (4,5) naphthalene-8-yl) phenyl acetamide], have optionally kappa agonist of K1; ((-)-17-encircles third methyl-3 to TRK-820,14b-dihydro-4,5a-epoxy-6b-[N-methyl-trans-3-(3-furyl) acrylamide] the morphinan hydrochloride) (TorayIndustries, Inc.Japan, potent kappa agonist, its pharmaceutical properties are different from those that the K1 receptor stimulating agent produced; Tifluadom is a benzodiazepine

The class kappa agonist (Sandoz, Inc., Princeton, N.J.); Or trans-3,4-two chloro-N-methyl-N-[1-(1-pyrrolidinyl) cyclohexyl] phenyl acetamide, United States Patent (USP) 4,758, the kappa agonist of describing in 562.

The kappa receptor agonist is disclosed in United States Patent (USP) 5,051,428; 5,965,701; 6,146,835; 6,191,126; 6,624,313; 6,174,891; 6,316,461; 6,440,987; 4,758,562; 6,583,151, the full text content of every piece of document is all incorporated this paper by reference into.

The predose of kappa receptor agonist is enough high to induce the counter adaptation effect, does not still have high to causing the patient direct effect that can not tolerate to occur.For example, the predose of kappa receptor agonist can be equal to the dynorphin that 0.0005-0.05mg/kg/ uses; The enadoline that 5-700mg/ uses; The FE20665 that 1-500 μ g/ uses; The U69 that 0.5-100 μ g/ uses, 0.01-1mg/kg/ uses, 593; 0.05-5mg/kg/ the TRK 820 that uses; 0.01-1mg/kg/ the PD117302 that U 50 488 that uses or 0.01-1mg/kg/ use.Desirably, the predose of kappa receptor agonist is equal to the dynorphin that 0.005-0.02mg/kg/ uses; The enadoline that 100-500mg/ uses; The FE 20665 that 3-100 μ g/ uses; The FE 20666 that 1-80 μ g/ uses; 0.1-0.7mg/kg/ the U69 that uses, 593; 0.5-3mg/kg/ the TRK820 that uses; 0.5-7mg/kg/ the PD 117302 that U 50 488 that uses or 0.1-0.7mg/kg/ use.

In another embodiment of the present invention, the kappa receptor agonist is Salvinorin A.Salvinorin A is new Roc alkane diterpene compound (neoclerodane diterpene compound), and it is very potent psychedelic drug, and it has the kappa agonist activity recent findings.Its not only represent known non--nitrogenous kappa agonist chemical compound.It is plant S.divinorum (Diviner ' s sage), the rare member's of Herba Menthae family main active.Since many centuries its by the Mazatec human of Mexico Oaxaca in ancient divine cure (spiritual practices).The predose of Salvinorin A is desirably used for 5-50 μ g/, and maximal dose desirably is that 5000 μ g/ use.But Salvornin A mucosal administration, or desirably in 2-6 hour persistent period, use as slow releasing preparation.

In embodiments more of the present invention, desirably administration for peptides kappa receptor agonist and non--peptide kappa receptor agonist.Can use two types agonist simultaneously or sequentially.

Peptide kappa receptor agonist can for example be used in intravenous, transdermal or through mucous membrane, as described to other peptide part.As described in to naloxone, desirably use mucosal administration (with the high-level ligand-receptor combination of rapid acquisition), and transdermal administration (so that the ligand-receptor combination of prolongation to be provided).

Because body is being used back antagonism in about 8 days opium generation tolerance for the first time, desirably can increase the dosage of kappa receptor agonist in time.For example, increase dosage in desirably can be during a week to two weeks.

The present invention uses in the example of method of Salvinorum A, and the predose of Salvinorum A is low to reduce possible side effect.Predose is 5 μ g-50 μ g.2-4 increases certain percentage ratio after week.This increase can be low to moderate 5-10% or more than the 50-100%.Usually, suggestion doubles predose.Therefore, 2-4 uses the Salvinorum A of 20-100 μ g after week to individuality.This dosage increases and continued in per 2,4,6 or 8 weeks.Also can continue to continue to increase on each season, every half a year or the annual basis.The dosage of 200 μ g can produce irritated effect.This sees acute administration.Slowly increase gradually dosage then side effect fade away.The maximal dose that slowly increases Salvinorum A in the situation of dosage gradually is 1000 μ g-5000 μ g or higher.

Use in the example of dynorphin analog in the present invention, use rectal suppository (saturating mucosa) preparation.Predose is enough high to induce the counter adaptive reaction, and is still enough low to minimize the irritated effect of causing of agonist-receptors bind.This suppository is two-part construct.Jacket layer is instant capacity and initial fast Absorption that allow the kappa receptor agonist compound.The second layer is destructive gradually so that slowly discharge other kappa receptor agonist, and it is absorbed gradually.This causes successive, the absorption slowly of peptide receptor agonist chemical compound.Be designed to absorb gradually lasting 6-8 hour, make to have 6-8 hour kappa receptor combination, induce counter adaptation during this period.This rectal suppository is based on using every day (night).2-4 after week doubles dosage.Using other 2-4-6-8 week of this dosage subsequently.The intermittent appearance that increases up to side effect of described dosage prevents further increase.Because this dosage increases, also prolong during the increase dosage, thereby before increasing dosage, may experience the several months.In addition, in case use higher dosage, the severe degree of increase is lower, and making only has the increase of 5-10%, rather than the doubling of starting dose.

Enadoline is non-peptide kappa receptor agonist.It has pharmaceutically active when taking with the oral dose of 1-10mg/kg.Use in the example of method of enadoline in the present invention, use the dosage of 100-200mg every day before the patient goes to bed.The 2-4 post dose is increased to 200-500mg.After 2-4 week, described dosage is increased to 500-1000mg.After 2,4,8 weeks or more time, described dosage is increased to 1500-2000mg.As long as side effect does not become uncontrollable, described dosage just can increase.

Desirably, the kappa receptor antagonist not with use the relevant very first time at every turn during in use.In embodiments more of the present invention, yet the kappa receptor antagonist is used in one or more second time durations.Representative kappa receptor antagonist comprises United States Patent (USP) 5,025,018; 5,922,887; With 6,284, the chemical compound of describing in 769.For 5,025, the chemical compound of describing in 018, appropriate dosage comprises that 0.1-10mg/ uses every day; For United States Patent (USP) 6,284,769, optimal dose comprises that 0.1-500mg/ uses.

Dynorphin neurotransmitter system and kappa receptor thereof and multiple bad spirit, nerve and physiological disorder positive correlation.The example of described disease comprises pain, mood disorders, eating disorders, anxiety neurosis, the motivation problem, psychoactive substance abuse, motivation or performance are not enough, the pain that expection occurs in the future (for example, because operation in the future or physical exertion in the future), chronic pain syndrome, acute pain, fibromyalgia, the chronic fatigue syndrome, long-term back pain, chronic headache, herpes zoster, reflex sympathetic dystrophy, neuropathy, inflammatory pain, long-term cancer pain, major depression sexual disorders, wound retarded depression disease, temporary depressive emotion, manic depression, dysthymic disorder, the popularity mood disorders, the sexual dysfunction of anhedonia or non-organic, gluttony, obesity, apositia or polyphagia, the generalized anxiety disorder state, panic disorder, Tourette's syndrome, hysteric sleep disease or the relevant sleep disease of breathing, because appearring in study or memory problems, motivation lacks, psychoactive substance abuse is (such as anesthetis, ethanol, nicotine, analeptic, antianxiety drug, the CNS inhibitor, psychedelic drug and Fructus Cannabis), the desirable spirit or the motivation of physical exertion or preparation are not enough (such as physical training, sports, study or test).The downward modulation of dynorphin system has poorly produced the treatment benefit to bad spirit, nerve or physiological disorder.

The 5-hydroxy tryptamine system

According to another embodiment of the present invention, the neurotransmitter system is the 5-hydroxy tryptamine system, and it comprises that 5-hydroxy tryptamine is as neurotransmitter.5-hydroxy tryptamine is a monoamine neurotransmitter.Low 5-hydroxy tryptamine level is with depressed relevant.Counter adaptation causes the rise of 5-hydroxy tryptamine system.

Identified multiple 5-hydroxytryptamine receptor (at least 14 kinds).The Cmax of 5-hydroxy tryptamine (90%) is arranged in gastrointestinal tract.The remaining most of 5-hydroxy tryptamine of body sees platelet and central nervous system (CNS).Acting in cardiovascular system, respiratory system and the intestinal of 5-hydroxy tryptamine is obvious.Vasoconstriction is the common reactant to 5-hydroxy tryptamine.

The function of 5-hydroxy tryptamine is by itself and the interaction of specific receptor demonstration.5HT has been cloned and be accredited as to 5-hydroxytryptamine receptor ₁, 5HT ₂, 5HT ₃, 5HT ₄, 5HT ₅, 5HT ₆And 5HT ₇At 5HT ₁Group in, have hypotype 5HT _1A, 5HT _1B, 5HT _1D, 5HT _1EAnd 5HT _1FThere are three kinds of 5HT ₂Hypotype 5HT _2A, 5HT _2BAnd 5HT _2CAnd two kinds of 5HT ₅Hypotype 5HT _5aAnd 5HT _5BMost of these receptors are coupled to the active G albumen that influences adenyl cyclase and phospholipase C g.The 5HT of receptor ₃Type is an ion channel.

Some 5-hydroxytryptamine receptors are presynaptic types, and other are postsynaptic types.5HT ₂Receptor-mediated platelet aggregation of A and smooth muscle contraction.Suspect 5HT _2CReceptor control is ingested, in default of the mice of this gene owing to ingest and increase and fat and the mortality epilepsy also takes place.5HT ₃Receptor is present in the gastrointestinal tract and is relevant with vomiting.There is the 5HT that also has in the gastrointestinal tract equally ₄Receptor, they are at this 5HT that works in secretion and wriggling ₆And 5HT ₇Receptor is distributed in the whole limbic system of brain, 5HT ₆Receptor has high affinity to antidepressant drug.

With emotion and depressed relevant modal 5-hydroxytryptamine receptor is first and second kinds, especially 5HT _1AReceptor.

When the 5-hydroxy tryptamine neuron triggered through stimulating, 5-hydroxy tryptamine was released into synapse.Some 5-hydroxy tryptamine molecules stride across synapse and in conjunction with postsynaptic receptor, it causes the neuronic triggering of postsynaptic 5-hydroxy tryptamine subsequently.5-hydroxy tryptamine causes its activation with neuronic combination of postsynaptic 5-hydroxy tryptamine, and it causes the relevant neurological events of a series of and overall good emotion.

When 5-hydroxy tryptamine discharged into synaptic space, only the part 5-hydroxy tryptamine was in fact in conjunction with postsynaptic receptor.Most of 5-hydroxy tryptamine molecule is removed from synapse by mechanism of absorption again.Wherein the part 5-hydroxy tryptamine is degraded by monoamine oxidase, MAO, the described enzyme 5-hydroxy tryptamine norepinephrine of also degrading of both having degraded.

The 3rd target of 5-hydroxy tryptamine molecule is a presynaptic autoreceptor.Described presynaptic autoreceptor is the inhibition receptor.Presynaptic autoreceptor works in the feedback suppression loop, and its function is the contrast mechanisms that neurotransmitter discharges.The feedback suppression loop is the common mode of body control neuronal activation.When they combined with 5-hydroxy tryptamine or agonist, they suppressed 5-hydroxy tryptamine and further discharge into synapse.Presynaptic autoreceptor is called 5HT _1AAnd 5HT _1BPresynaptic autoreceptor.5HT _1AThe tonicity that autoreceptor suppresses 5-hydroxy tryptamine discharges (tonic release).5HT _1BAutoreceptor is considered to suppress the release that is stimulated of 5-hydroxy tryptamine and synthesize.

If the neurotransmitter system is the 5-hydroxy tryptamine system, acceptor type for example can be, and the 5-hydroxy tryptamine presynaptic autoreceptor is such as 5HT _1AAutoreceptor or 5HT _1BAutoreceptor.In described situation, part is a 5-hydroxy tryptamine presynaptic autoreceptor agonist, described bad spirit, nerve or physiological disorder and receptor positive correlation.Counter adaptation for example can be, and 5-hydroxy tryptamine increases in the biosynthesis and/or the release of synaptic space; 5-hydroxy tryptamine absorbs minimizing again; 5-hydroxy tryptamine presynaptic autoreceptor decreased number; The 5-hydroxy tryptamine presynaptic autoreceptor reduces the sensitivity of 5-hydroxy tryptamine and/or 5-hydroxy tryptamine presynaptic autoreceptor agonist; The number of 5-hydroxy tryptamine postsynaptic receptor increases; The 5-hydroxy tryptamine postsynaptic receptor increases the sensitivity of 5-hydroxy tryptamine or 5-hydroxy tryptamine postsynaptic receptor agonist; Or its any combination.

Multiple 5-hydroxy tryptamine presynaptic autoreceptor agonist can be used in the method for the present invention.For example, 5-hydroxy tryptamine presynaptic autoreceptor agonist can be EMD-68843, buspirone (buspirone), gepirone, ipsapirone, tandospirone, lesopitron, zalospirone, MDL-73005EF or BP-554.

Desirably, the predose of 5-hydroxy tryptamine presynaptic autoreceptor agonist is enough high to induce the counter adaptation effect, does not still have high to causing the patient direct effect that can not tolerate to occur.For example, the predose of 5-hydroxy tryptamine presynaptic autoreceptor agonist can be equal to EMD-68843, the buspirone that 1-500mg/ uses, the lesopitron that 1-500mg/ uses, the gepirone that 1-500mg/ uses, the tandospirone of 5-500mg or the zalospirone of 1-200mg that 1-400mg/ uses.Desirably, the predose of 5-hydroxy tryptamine presynaptic autoreceptor agonist is equal to EMD-68843, the buspirone that 10-100mg/ uses, the lesopitron that 10-200mg/ uses, the gepirone that 10-100mg/ uses, the tandospirone of 20-200mg or the zalospirone of 10-100mg that 10-100mg/ uses.

Desirably, 5-hydroxy tryptamine presynaptic autoreceptor antagonist not with use the relevant very first time at every turn during in use.Yet in embodiments more of the present invention, 5-hydroxy tryptamine presynaptic autoreceptor antagonist is used in one or more second time durations.Representative 5-hydroxy tryptamine presynaptic autoreceptor 5HT1A agonist and antagonist comprise Elazonan, and AR-A2 (AstraZeneca, London, UK); AZD-1134[AstraZeneca, London, UK); Pindolol, and US 6,462,048; 6,451,803; 6,627,627; 6,602,874; 6,277,852; With 6,166, the chemical compound of describing in 020, it incorporates this paper in full by reference into.

In another embodiment of the present invention, acceptor type is the 5-hydroxy tryptamine postsynaptic receptor, such as 5HT ₁Receptor; 5HT ₂Receptor; 5HT ₃Receptor; 5HT ₄Receptor; 5HT ₅Receptor; 5HT ₆Receptor; 5HT ₇Receptor; Or the receptor of its hypotype.Part is a 5-hydroxy tryptamine postsynaptic receptor antagonist.Common and these receptor negative correlation of bad spirit, nerve or physiological disorder.Counter adaptation can be 5-hydroxy tryptamine to be increased in the biosynthesis and/or the release of synaptic space; 5-hydroxy tryptamine absorbs minimizing again; 5-hydroxy tryptamine postsynaptic receptor number increases; The 5-hydroxy tryptamine postsynaptic receptor increases the sensitivity of 5-hydroxy tryptamine and/or 5-hydroxy tryptamine postsynaptic receptor agonist; 5-hydroxy tryptamine presynaptic autoreceptor decreased number; The 5-hydroxy tryptamine presynaptic autoreceptor reduces the sensitivity of 5-hydroxy tryptamine and/or 5-hydroxy tryptamine presynaptic autoreceptor agonist; Or its any combination.

Multiple chemical compound can be used as the 5-hydroxy tryptamine postsynaptic receptor antagonist among the present invention.For example, 5-hydroxy tryptamine postsynaptic receptor antagonist can be (S)-WAY-100135, WAY-100635, buspirone, gepirone, ipsapirone, tandospirone, lesopitron, zalospirone, MDL-73005EF or BP-554.If desirable, SSRI can simultaneously or in turn use with aforementioned 5-hydroxy tryptamine regulator.This has certain advantage, because SSRI and agonist presynaptic counter adaptation therapy cause the downward modulation of presynaptic receptor.The SSRI effect is amplified by described counter adaptation effect thus.Secondly, the downward modulation of the postsynaptic 5-hydroxytryptamine receptor that occurs with the SSRI therapy can remedy by postsynaptic antagonist counter adaptation therapy.

The predose of 5-hydroxy tryptamine postsynaptic antagonist is desirably enough high to induce the counter adaptation effect, and is still not high to causing the patient direct effect that can not tolerate to occur.For example, the predose of 5-hydroxy tryptamine postsynaptic receptor antagonist is equal to the WAY-100635 that about 0.01-5mg/kg/ uses.Desirably, the predose of 5-hydroxy tryptamine postsynaptic receptor antagonist is equal to the WAY-100635 that about 0.025-1mg/kg/ uses.

5-hydroxy tryptamine postsynaptic receptor antagonist can be co-administered with 5-hydroxy tryptamine presynaptic autoreceptor agonist, all as indicated above those.In addition, when in conjunction with the conventional antidepressant medicament of 5-hydroxy tryptamine postsynaptic receptor and 5-hydroxy tryptamine presynaptic autoreceptor agonist when co-administered, its effectiveness can increase greatly, and this is because quantity and the sensitivity of 5-hydroxy tryptamine postsynaptic receptor by counter adaptation increases.

In desirable embodiments more of the present invention, 5-hydroxy tryptamine postsynaptic antagonist itself also is a 5-hydroxy tryptamine presynaptic autoreceptor agonist.With norepinephrine presynaptic alpha-2 adrenergic receptor agonists and/or norepinephrine postsynaptic adrenergic aceptor antagonist (as mentioned below) and 5-hydroxy tryptamine postsynaptic antagonist or 5-hydroxy tryptamine presynaptic autoreceptor agonist co-administered also be desirable.

Desirably, 5-hydroxy tryptamine postsynaptic receptor agonist not with use the relevant very first time at every turn during in use.But in some embodiments of the present invention, 5-hydroxy tryptamine postsynaptic receptor agonist is used in one or more second time durations.Representative 5-hydroxy tryptamine postsynaptic receptor agonist comprises BIMT17 (1-[2-[4-(3-trifluoromethyl) piperazine-1-yl] ethyl] benzimidazole-[1H]-2-ketone), dosage: 1-10mg/kg (i.v or transdermal, SQ etc.).See Borsini, F, etc., Archives of Pharmacology, 352 (3); Sept, 1995:283-290.].The appropriate dosage scope comprises the BIMT17 (via iv, transdermal or SQ) that 1-10mg/kg/ uses.

The common negative of 5-hydroxy tryptamine postsynaptic receptor about, the 5-hydroxy tryptamine presynaptic autoreceptor is positively correlated with multiple bad spirit, nerve and physiological disorder usually.The example of described disease comprises pain, mood disorders, eating disorders, anxiety neurosis, obsession, the motivation problem, psychoactive substance abuse, motivation or performance are not enough, the pain that expection occurs in the future (for example, because operation in the future or physical exertion in the future), chronic pain syndrome, acute pain, fibromyalgia, the chronic fatigue syndrome, long-term back pain, chronic headache, herpes zoster, reflex sympathetic dystrophy, neuropathy, inflammatory pain, long-term cancer pain, major depression sexual disorders, wound retarded depression disease, temporary depressive emotion, manic depression, dysthymic disorder, the popularity mood disorders, the sexual dysfunction of anhedonia or non-organic, gluttony, obesity, apositia or polyphagia, the generalized anxiety disorder state, panic disorder, Tourette's syndrome, hysteric sleep disease or the relevant sleep disease of breathing, because appearring in study or memory problems, motivation lacks, psychoactive substance abuse is (such as anesthetis, ethanol, nicotine, analeptic, antianxiety drug, the CNS inhibitor, psychedelic drug and Fructus Cannabis), the desirable spirit or the motivation of physical exertion or preparation are not enough (such as physical training, sports, study or test).The rise of 5-hydroxy tryptamine system has desirably produced the treatment benefit to bad spirit, nerve or physiological disorder.

The norepinephrine system

In another embodiment of the present invention, the neurotransmitter system is the norepinephrine system, and it comprises norepinephrine as neurotransmitter, and counter adaptation causes the rise of norepinephrine system.

Norepinephrine is a catecholamine, and it plays neurotransmitter with epinephrine in the central nervous system.There is two types adrenoceptor, α and β.At least the adrenoceptor that also has 10 kinds of different subtypes.In general norepinephrine is excitatoty and more effective by receptor-alpha mediated site at the sympathetic nerve mediator.The α receptor has two kinds of hypotypes, α 1 and α 2.

Norepinephrine plays neuromodulator in the central nervous system.The central nervous system of NE acts on that it is the most remarkable when regulating excitability or inhibition input, rather than it acts on the activity of postsynaptic target, when lacking other input.Norepinephrine transmission and control are similar to the situation of 5-hydroxy tryptamine.Have mechanism of absorption again, it removes most of norepinephrine after it discharges into the adrenergic synapse.Known presynaptic inhibition autoreceptor is an alpha-2 adrenergic receptor.

If the neurotransmitter system is the norepinephrine system, acceptor type can be for example norepinephrine presynaptic alpha-2 adrenergic receptor.In described situation, part is a norepinephrine presynaptic alpha-2 adrenergic receptor agonists.Common and the receptor positive correlation of bad spirit, nerve or physiological disorder.Counter adaptation can be norepinephrine to be increased in the biosynthesis and/or the release of synaptic space; Norepinephrine absorbs minimizing again; Norepinephrine presynaptic alpha-2 adrenergic receptor decreased number; Norepinephrine presynaptic alpha-2 adrenergic receptor reduces the sensitivity of norepinephrine and/or norepinephrine presynaptic alpha-2 adrenergic receptor agonists; The number of norepinephrine postsynaptic adrenoreceptor increases; Norepinephrine postsynaptic adrenoreceptor increases the sensitivity of norepinephrine and/or norepinephrine postsynaptic 3 adrenergic receptor agonists; Or its any combination.

Multiple chemical compound can be used as the norepinephrine presynaptic alpha-2 adrenergic receptor agonists in the inventive method.For example, norepinephrine presynaptic alpha-2 adrenergic receptor agonists can be clonidine, guanfacine, lofexidine, detomidine, dexmedetomidine, mivazerol or Alpha-Methyl norepinephrine ((methylnoradreniline)).

The predose of norepinephrine presynaptic alpha-2 adrenergic receptor agonists is desirably enough high to induce the counter adaptation effect, does not still have high to causing the patient direct effect that can not tolerate to occur.For example, described predose can be equal to the clonidine that 0.1 and 10 μ g/kg/ use, 0.01-10mg/ the guanfacine of using, 0.01-1mg/ the lofexidine of using, the detomidine that 1-100 μ g/kg/ uses, 0.05-5 the dexmedetomidine that μ g/kg/ uses, the mivazerol that 0.05-10 μ g/kg/ uses, or the Alpha-Methyl norepinephrine used of 5-500ng/kg/.Desirably, described predose is equal to the clonidine that 0.1-0.5mg/ uses, 0.1-5mg/ the guanfacine of using, 0.05-0.5mg/ the lofexidine of using, the detomidine that 10-80 μ g/kg/ uses, 0.1-3 the dexmedetomidine that μ g/kg/ uses, the mivazerol that 0.5-5 μ g/kg/ uses, or the Alpha-Methyl norepinephrine used of 10-100ng/kg/.

Desirably, norepinephrine presynaptic alpha-2 adrenergic receptor antagonist not with use the relevant very first time at every turn during in use.But in some embodiments of the present invention, norepinephrine presynaptic alpha-2 adrenergic receptor antagonist is used in one or more second time durations.The suitable limiting examples of presynaptic and back A2AR antagonist comprises mirtazapine (mirtazapine).

According to another embodiment of the present invention, acceptor type is a norepinephrine postsynaptic adrenoreceptor, such as the α receptor, and beta receptor, or the receptor of its hypotype.In described situation, part is a norepinephrine postsynaptic adrenergic aceptor antagonist.Common and the norepinephrine postsynaptic adrenoreceptor negative correlation of bad spirit, nerve or physiological disorder.Counter adaptation can be norepinephrine to be increased in the biosynthesis or the release of synaptic space; Norepinephrine absorbs increase again; Norepinephrine postsynaptic adrenoreceptor number increases; Norepinephrine postsynaptic adrenoreceptor reduces the sensitivity of norepinephrine and/or norepinephrine postsynaptic 3 adrenergic receptor agonists; Norepinephrine presynaptic alpha-2 adrenergic receptor decreased number; Norepinephrine presynaptic alpha-2 adrenergic receptor reduces the sensitivity of norepinephrine and/or norepinephrine presynaptic alpha-2 adrenergic receptor agonists; Or its any combination.

Multiple chemical compound can be used as the norepinephrine postsynaptic adrenergic aceptor antagonist among the present invention.For example, described norepinephrine postsynaptic adrenergic aceptor antagonist can be idazoxan, SKF 104078 or SKF 104856.The predose of norepinephrine postsynaptic adrenergic aceptor antagonist is advantageously enough high to induce the counter adaptation effect, and is still not high to causing that the patient is produced the direct effect that can not tolerate.For example, predose can be equal to the idazoxan that 0.5-100mg/ uses.Desirably, described predose is equal to the idazoxan (idazoxan) that 5-50mg/ uses.

Desirably, norepinephrine postsynaptic 3 adrenergic receptor agonists not with use the relevant very first time at every turn during in use.But in embodiments more of the present invention, norepinephrine postsynaptic 3 adrenergic receptor agonists is used in one or more second time durations.

Norepinephrine postsynaptic adrenergic aceptor antagonist can all as indicated above those be co-administered together with norepinephrine presynaptic alpha-2 adrenergic receptor agonists.In addition, when can be when the norepinephrine presynaptic, alpha-2 adrenergic receptor agonists be co-administered in conjunction with the conventional antidepressant medicament of norepinephrine postsynaptic adrenoreceptor, its effectiveness can improve greatly since norepinephrine postsynaptic adrenoreceptor by its number of counter adaptation and/sensitivity increases.

In some desirable embodiments of the present invention, norepinephrine postsynaptic adrenergic aceptor antagonist itself also is a norepinephrine presynaptic alpha-2 adrenergic receptor agonists.With 5-hydroxy tryptamine postsynaptic antagonist and/or 5-hydroxy tryptamine presynaptic autoreceptor agonist (as mentioned above) and norepinephrine presynaptic alpha-2 adrenergic receptor agonists or norepinephrine postsynaptic adrenergic aceptor antagonist co-administered also be desirable.

The common negative of norepinephrine postsynaptic adrenoreceptor is positively correlated with multiple bad spirit, nerve and physiological disorder usually about, norepinephrine presynaptic alpha-2 adrenergic receptor.The example of described disease comprises pain, mood disorders, eating disorders, anxiety neurosis, obsession, the motivation problem, psychoactive substance abuse, motivation or performance are not enough, the pain that expection occurs in the future (for example, because operation in the future or physical exertion in the future), chronic pain syndrome, acute pain, fibromyalgia, the chronic fatigue syndrome, long-term back pain, chronic headache, herpes zoster, reflex sympathetic dystrophy, neuropathy, inflammatory pain, long-term cancer pain, major depression sexual disorders, wound retarded depression disease, temporary depressive emotion, manic depression, dysthymic disorder, the popularity mood disorders, the sexual dysfunction of anhedonia or non-organic, gluttony, obesity, apositia or polyphagia, the generalized anxiety disorder state, panic disorder, Tourette's syndrome, hysteric sleep disease or the relevant sleep disease of breathing, because appearring in study or memory problems, motivation lacks, psychoactive substance abuse is (such as anesthetis, ethanol, nicotine, analeptic, antianxiety drug, the CNS inhibitor, psychedelic drug and Fructus Cannabis), the desirable spirit or the motivation of physical exertion or preparation are not enough (such as physical training, sports, study or test).The rise of norepinephrine system is desirably led bad spirit, nerve or physiological disorder has been produced the treatment benefit.

The CRF system

Hypothalamic-pituitary-adrenal (HPA) axle be the health response stress regulatory mechanism.Hypothalamus is total control centre of multiple health hormone.In response to stress, hypothalamus discharges corticotropin-releasing factor (CRF, be also referred to as corticotropin releasing hormone), it arrives anterior pituitary and induces hormone ACTH (thyroliberin) and beta-endorphin are released into the circulation variation.ACTH arrives and is positioned at the adrenal gland who is adjacent to kidney, and stimulates the release of hydrocortisone (cortisol).Hydrocortisone be released into loop start a series of alleviate stress the metabolic effect of illeffects.Also have for the antepituitary of closing other hydrocortisone release and the negative feedback of hypothalamus.

Except discharging from hypothalamic CRF, CRF is present in many other zones of cortex.When its when hypothalamus discharges, it is as hormone.In cortex, the CRF molecule is as neurotransmitter.The neurotransmitter effect of CRF causes some behavior effects (behavioral effect) common in the depression.In these effects some are owing to the influence of CRF for other neurotransmitter system (as 5-hydroxy tryptamine and norepinephrine (NE) system).CRF is with depressed related thereby be unusual complexity, and relates to it for the effect of hpa axis and for brain with for the direct effect of other neurotransmitter system.

CRF is 41 amino acid peptides.It was at first separated and (the Vale W that checks order by Vale in 1981, Spiess J, Rivier C, Rivier J (1981): Characterization of a 41-residue ovinehypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin .Science 213:1394-1397).Measured the sequence of CRF in a plurality of species, described species comprise sheep, people, rat, pig, goat and cattle.In all species, CRF is a 41-amino acid residue single chain polypeptide.Rat and people CRF be equal to each other and differ the seven amino acid residue with the CRF of sheep.All three kinds of CRF have approaching amino acid identity and share some biological properties with sauvagine (sauvagine) with urotensin I (urotensin I), wherein sauvagine is 40 amino acid whose peptides that are present in the frog skin, and urotensin I is 41 amino acid whose peptides that are derived from fish urine hypophysis (urophysis).Goat and CRF sheep be equal to and differ an aminoacid with cattle CRF.The closer similar rat of the CRF of pig/people CRF.CRF and the c-terminus amidatioon of relevant peptide at them; CRFCOOH-end-free acid has the effectiveness less than 0.1% natural CRF, and this shows the bioactive importance of amidatioon for peptide.Use proton magnetic resonance (PMR) spectrum determine CRF solution structure (solutionstructure) studies show that people CRF comprise with residue 6 to 36 between the N-end tetrapeptide of the prolongation that links to each other of clear and definite alpha-helix.The oCRF of alpha-helix (9-41) is the antagonist of CRF, it emphasizes that alpha-helix conformation is for receptors bind and bioactive necessity (Errol B.De Souza and Dimitri E.Grigoriadis, Corticotropin-Releasing Factor:Physiology, Pharmacology and Rolein Central Nervous System and Immune Disorders, Psychopharmacology-FourthGeneration of Progress, 2000, http://neurotransmitter.net/newdrugs.htmlhttp: //www.acnp.org/g4/GN401000049/CH049.html " Treatments for Depressionand Anxiety ").

Emotion, mood disorders and associated conditions are the results of the complex network of central nervous system's incident, and described central nervous system's incident is relevant with many neurotransmitteies system.Modal mood disorders is depressed.Depression is the clinical diagnosis with multiple body and mental symptom, and it is because the change of various neurotransmitters system causes.Except that the CRF system, other system relevant with depression is norepinephrine, 5-hydroxy tryptamine, P material, dynorphin (kappa receptor) and endogenous endorphins (μ and delta opiate receptor) system.In addition, these neurotransmitter systems are also relevant with the whole host of other bad spirit, nerve and physiological disorder, and described disease comprises biphasic or bipolar type mental disorder, obsession, anxiety, phobia, stress disorders, psychoactive substance abuse, sexual dysfunction, eating disorders, motivation obstacle and pain obstacle.

The main cause of depression and anxiety in stress being considered to be grown up.Individual in fact whether to become depressed clinically genetic factor and any important early stage stressful situation (Lott, Psychiatric Times 1999 Oct that also depend on depression; Vol.XVI, Issue 10.).

Hpa axis plays an important role because of its acting in depressed and the anxiety disorder in stressful situation.It is well-established that to be the CRF level increase in depressed (that is, inhibitable type depressed but be not atypical depression-see below).Cortisol levels also increases in depression usually.This is because the hyperkinesia of hpa axis, mainly is considered to because the damage in negative inhibition loop causes.In other words, the lasting release of CRF and the lasting rising in circulation thereof can be the result of chronic stress situation, and the inhibition of the cortisol levels that is not raise, as what in normal, non-depressed individuality, exist.

Depressed research is divided into a class with all patients usually.Yet multi-form depression is arranged, and it tends to have different adjustings and changes in hpa axis.There are two kinds of significant depressed hypotypes, the depressed and atypical depression of inhibitable type.The inhibitable type depression is depressed modal form.The inhibitable type patient normally anxiety, worry following, forfeiture to the responsiveness of environment, suffer from insomnia, forfeiture appetite (losing weight) and variation (depression is the most serious in the morning) round the clock.Atypical patient a plurality of be opposite usually in aspect these.Superfluous (hypersomnic) of that atypical patient is normally drowsiness, tired, bulimiac (weight increase), sleep, to environment reaction, and depressed variation round the clock (depression the is the slightest in the morning) (Gold of demonstration, Deng, " Organization of the stress system and itsdysregulation in melancholic and atypical depression:high vs.low CRH/NEstates. " Mol Psychiatry, 2002; 7 (3): 254-75. ").

The inhibitable type patient is characterised in that ergogenic maincenter CRH system, has the hyperkinesia (over-activity) of hpa axis.On the other hand, atypical depression is characterised in that Underactivity (the under-activity) (Kasckow of hypoactive maincenter CRH system and hpa axis, JW, Deng, " Corticotropin-releasing hormone in depression and post-traumatic stressdisorder. " Peptides, 2001 May; 22 (5): 845-51.).Atypical depression is considered to because the excessive inhibition (hyper-suppression) of hpa axis causes.It can regulate relevant (Levitan RD with the excessive negative feedback of hpa axis, " Low-dose dexamethasone challenge in women withatypical major depression:pilot study. " J Psych Neurosci, 2002 Jan; 27 (1): 47-51).

Stress disorders after the wound (PTSD) is that the 3rd class and it also are unique.PTSD is characterised in that as the ergogenic maincenter CRH system in the inhibitable type depression, but exists as the Underactivity (Levitan, 2002) of the hpa axis in atypical depression.

Anxiety disorder has and the depressed different hpa axis changing pattern of inhibitable type.Depressed be characterised in that the non-inhibition behind high hydrocortisone mass formed by blood stasis (hypercortisolaemia), the dexamethasone (dexamethasone) and the minimizing of glucocorticoid receptor (GR) number.Anxiety is characterised in that the super inhibition (super-suppression) behind low hydrocortisone mass formed by blood stasis (hypo-cortisolemia), the dexamethasone and the increase (Boyer of glucocorticoid receptor (GR) number, P, " Do anxiety and depression have a commonpathophysiological mechanism? " Acta Psychiatr Scand Suppl 2000; (406): 24-9).

Eating disorders relates generally to emotion and/or stress.Dallman etc., (Chronic stress andobesity:a new view of " comfort food " .Proc Natl Acad Sci USA 2003 Sep 30; 100 (20): 11696-701) proof, although rat reduces body weight usually in response to chronic stress, the chronic stress of philtrum is induced increase and the weight increase or the picked-up minimizing of instant food picked-up and is lost weight.As discussed above, the inhibitable type depression tend to the appetite difference and lose weight relevant, and atypical depression tend to take food increase relevant with weight increase.

The conventional strategy that is used for the treatment of the disease relevant with neurotransmitter concentrates on the unusual high or low level of improving the synapse neurotransmitter.The conventional therapy agent is used for directly regulating the function of neurotransmitter system.These agents can be antianxiety drug, somnifacient or selectivity reuptake inhibithors, and comprise benzodiazepine

Class (for example diazepam (diazepam), lorazepam (lorazepam), alprazolam (alprazolam), temazepam (temazepam), flurazepam (flurazepam) and chlordiazepoxide), TCAs, MAOIs, SSRIs (for example, fluoxetine hydrochloride), NRIs, SNRIs, 5-hydroxy tryptamine presynaptic autoreceptor antagonist, 5HT ₁Agonist, GABA-A regulator, 5-hydroxy tryptamine 5H _2CAnd/or 5H _2BRegulator, β-3 adrenoceptor agonists, nmda antagonist, V1B antagonist, GPCR regulator, dynorphin antagonist and P substance antagonist.The CRF antagonist is considered to next type (Nielsen, Life Sci, 2006, the Jan25 of antidepressants; 78 (9): 909-19.).

With regard to the CRF system, because the different hpa axis of different depressed types change, expection depends on the type of the depression for the treatment of or anxiety disorder for replying of drug effect agent and changes.In fact, effectively reduce the antidepressants that CRH produces, promptly TCAs has the favorable effects for the inhibitable type depression.These identical agents are not effective especially for the atypical depression of treatment, its activation with the system that produces CRH is uncorrelated, and relevant (Licinio with the excretory minimizing of CRH, J, Deng, " Roleof corticotrophin releasing hormone 41 in depressive illness. " Baillieres ClinEndocrinol Metab, 1991 Mar; 5 (1): 51-8.).

A lot of research point out the CRF antagonist as the potentiality of antidepressants (O ' brien, HumPsychopharmacol, 2001, Jan; 16 (1): 81-87 and Arborelius, etc., J Endocrinol 1999,160:1-12).Because they block the effect of ergogenic CRF system, the CRF antagonist is considered to indicate the disease (as the inhibitable type depression) with ergogenic CRF system, and the disease (as atypical depression) of not indicating the CRF system with function decay.

Beta-endorphin is an endogenous opiate chemical compound useful in the stress process.It reduces the sensation of pain.Endorphins be guarantee it at first is survival, secondly be the result of the evolutionary mechanism that recovers.Pain will produce the behavior of injury chance of surviving usually.For example, if animal is under attack and stop to lick and lick its wound and do not flee from its assailant, then the life of animal is on the line.But, the frightened release that triggers endorphins, the perception of its inhibition of pain.In addition, if animal is injured, endorphins has effect for the immune system that helps better to avoid infection, and this is favourable.

β endorphins and HPA are closely related.Except the effect for the zone in the cortex of brain of β endorphins, as improving pain reaction, the β endorphins is the release (figure X) by regulate CRF in hypothalamic negative inhibition also.

β endorphins and endogenous opioid peptide suppress HPA (Burnett, J Affect Disord 1999 Jun by the release that reduces CRF usually; 53 (3): 263-8.).The situation (tone) that studies have shown that of back exists the inhibition opioid to reduce in the individuality of depression.In other words in the individuality of depression, there is the downward modulation of β endorphins system.This obtains confirming (Cohen, AM J Psychiatry 1984 by showing depressed other research relevant with the cyclical level reduction of β endorphins; 141:629-32., andDjurovic, Farmaco 1999 Mar 31; 54 (3): 130-3.).

Show that also the β endorphins increases (Goodwin, J Affect Disord 1993Dec in the individuality of depression; 29 (4): 281-9).Though the above-mentioned research that this discovery seems with the endorphins level reduces in depression contradicts, back one research is in fact consistent with above-mentioned research.It is explained as follows.In one research (Goodwin) of back, the β endorphins in fact with the seriousness negative correlation of depressive symptom, it is in harmonious proportion the depressed relevant fact and above-mentioned research (Cohen with β endorphins following; Djurovic) be consistent.The violent psychosocial unexpected strike (acute psychosocial precipitant) that studies show that of Goodwin can increase β endorphins level sharp.This shows that the acute stress incident can cause CRF to increase and make it can surpass the downward modulation of β endorphins system.Yet the research of Goodwin also confirms the following fact: there is common downward modulation in the β endorphins because of depressed, and the depressed seriousness and the horizontal reverse correlation of circulation β endorphins, just like what shown by Cohen and Djurovic institute.In a word, though the β endorphins can raise in the depressed individuality that stands the incident of stress hitting suddenly sharp, for daily steady state levels, depressed patient has the circulation endorphins that is lower than normal level.

The research summary of Burnett (1999) some depressed clinically individual available opiate Heal Thyselfs.In these situations, opiate replaces the endogenous endorphins of ' losing ' or downward modulation.The opiate that these oneselfs use carries out the identical work done with the endogenous endorphins, and its meaning is to suppress HPA, reduces CRF thus and discharges.

Because the superfunction of HPA uses the CRF antagonist to be used for depressed treatment with depressed relevant so advocate recently.For using CRF antagonist for treating depression that some restrictions are arranged.

Therefore, in one embodiment of the invention, the neurotransmitter system is the CRF system, it induces corticotropin-releasing factor as neurotransmitter, the receptor of described type is the CRF receptor, and part is the CRF receptor stimulating agent, and counter adaptation causes the downward modulation of CRF system.Regulating the CRF system via counter adaptation submits to and is entitled as in the U.S. Provisional Patent Application serial number 60/777,190 of " METHOD OF REGULATING THECRF AND AVP SYSTEMS BY INDUCING COUNTERADAPTATIONS " on February 27th, 2006 and describe.

The CRF receptor can be, for example, and CRF-1 or CRF-2.CRF-1 is relevant with emotion usually, and CRF-2 is relevant with memory usually.

The CRF agonist all has influence to HPA and outer (extra-hypothalamic) system of hypothalamus.With respect to HPA, the CRF agonist causes ACTH and β endorphins to be released into circulation.In (near-term) of short-term is provided with (that is, and with use the relevant very first time at every turn during in), the release of β endorphins is useful, because known endorphins improves ergogenic CRF disease, as depression and anxiety.But the CRF agonist also can increase ACTH to be discharged, and it can have increases the effect that hydrocortisone discharges in the recent period.The rising of hydrocortisone be not when target be needed when suppressing ergogenic CRF system active.In addition, agonist direct effect CRF system outside hypothalamus.Together, discharge and cause the deterioration of ergogenic CRF state in the short-term for the effect of outer CRF of hypothalamus and AVP system for ACTH.Yet according to the present invention, method as herein described causes total downward modulation of counter adaptation and CRF system, is for example undertaken by downward modulation ACTH release and the outer CRF system of downward modulation hypothalamus.

Counter adaptation can be corticotropin-releasing factor to be reduced by hypothalamic biosynthesis or release; The decreased number of the binding site on the number of CRF receptor and/or the CRF receptor; Described receptor pair reduces with CRF receptor stimulating agent and/or the bonded sensitivity of corticotropin-releasing factor; Or their any combination.

Multiple chemical compound can be used as the CRF receptor stimulating agent.For example, many chemical compounds based on peptide are CRF receptor stimulating agents.The analog that example comprises corticotropin-releasing factor with and pharmaceutically useful salt and derivant.Cortagine is the appropriate C RF receptor stimulating agent that is used for method of the present invention, at Tezval, etc., PNAC, 101 (25) (2004) and Todorovic, C., etc., Neurosci BiobehavRev., 2005,29 (8): describe among the 1323-1333, every piece of document is incorporated this paper by reference into.The example of CRF receptor stimulating agent is in United States Patent (USP) 5,132,111; 5,278,146; 5,824,771; 5,844,074; 6,214,797; 6,670,371; 6,812,210; Further describe in 6,953,838, its every piece document is incorporated this paper thus by reference into.

The predose of CRF receptor stimulating agent desirably for enough height inducing the counter adaptation effect, but be not so high so that the patient produces intolerable direct effect.For example, predose can be about 0.1 to 100 μ g/kg/ days predose and 100 to 1000 μ g/kg/ days, continues 8 hours slow release.In some embodiments of the present invention, the predose of CRF receptor stimulating agent is about 1 to 50 μ g/kg/ days predose and 20 to 50 μ g/kg/ days, continues 8 hours slow release.

Desirably, neither use the CRF receptor antagonist in during the very first time relevant, also do not use the AVP receptor antagonist with use the CRF receptor stimulating agent at every turn.Yet in some embodiments of the present invention, CRF receptor antagonist and/or AVP receptor antagonist are used in one or more second time durations relevant with use the CRF receptor stimulating agent at every turn.

The example of CRF antagonist comprises R121919 (Zobel, J Psychiatr Res 2000 May-Jun; 34 (3): 171-81), DMP696 (Maciag, Neuropsychopharmacol 2002; 26:574-582), antalarmin (Willenberg, Mol Psychiatry 2000 Mar; 5 (2): 137-41), CP-154,526 (Mansbach, Eur J Pharmacol 1997 Mar 26; 323 (1): 21-6), SSR125543A (Briebel, J Pharmacol Exp Ther 2002 Apr; 301 (1): 333-45), 2-arylamino-4-trifluoromethyl-amino methyl thiazole antagonist (Dubowchik, Bioorg Med Chem Lett 2004 Nov 17; 13 (22): 3997-4000) and astressin (Spina, Neuropsychopharmacol 2000; 22:230-239) and their pharmaceutically useful salt, analog and derivant.

The example of AVP receptor antagonist comprises the AVP receptor antagonist of peptide, as d (CH2) 5Tyr (Me) AVP, Phaa-d-Tyr (Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH ₂, [Lys (3N ₃Phpa) ⁸] HO-LVA, [d (CH2) 5, D-Ile2, Ile4]-AVP and [ ¹²⁵I]-d (CH2) 5[D-Tyr (Et) 2, Val4, Tyr-NH29] AVP and have any analog of the AVP peptide (Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly) of AVP antagonist activities.The AVP peptide antagonists can further comprise any propetide (pro-peptide) molecule, and it is cut into active AVP antagonist by enzyme.The example of AVP receptor antagonist also comprises the kind of non-peptide, as OPC-21268OPC-21268 (1-(1-[4-(3-acetyl-amino propoxyl group) benzoyl]-4-piperidyl)-3,4-dihydro-2 (1H)-quinolinone); R49059 (V1a antagonist); OPC-31260 (5-dimethylamino-1-[4-(2-methyl benzoyl amino) benzoyl]-2,3,4,5-tetrahydrochysene-1H-benzo-aza

); Conivaptan (YM087-a V1a and V2 antagonist), Vaprisol (conivaptan) (V1a and V2 antagonist), VPA985 (V2 antagonist) and YM471[(Z)-4 '-[4,4-two fluoro-5-[2-(4-dimethylamino piperidino)-2-oxo ethylidene]-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza

-1-carbonyl]-2-phenyl benzanilide mono-hydrochloric salts].The AVP receptor antagonist is also at United States Patent (USP) 6,627, describes in 649 and 6,495,542, and its every piece document is incorporated this paper thus by reference into.

In another embodiment of the invention, μ and/or delta opiate receptor antagonist and CRF agonist is co-administered in during the very first time, its use half life and use between during ratio be not more than 1/2.The application process of μ and/or delta opiate receptor antagonist is above being described.This can be desirable due to the fact that: the use of CRF agonist though be intended to cause the downward modulation of CRF system, can have also with the unintentional result of β endorphins from the release downward modulation of anterior pituitary.Such endorphins discharges and reduces the required opposite effect of bad disease (as depression and anxiety disorder) that will cause with the horizontal reverse correlation of improvement and circulation endorphins.The repetitive administration opiate antagonist can have two kinds of important effects: blocking-up is by the downward modulation of the endorphins of CRF receptor stimulating agent, causes the rise of aforesaid endorphins system in addition.It is as indicated above with the principle of inducing endogenous endorphins system to raise to use opiate antagonist.As mentioned above, desirable is to use CRF and/or AVP antagonist in second time durations relevant with use the CRF agonist at every turn.Desirably, with use the relevant very first time at every turn during in neither use the CRF receptor antagonist, do not use the AVP receptor antagonist yet.

Use according to the CRF agonist of this embodiment of the present invention and can be used for treating bad spirit, nerve or physiological disorder among the patient, described bad spirit, nerve or physiological disorder and CRF receptor positive correlation.With CRF receptor positive correlation and can use the example of bad spirit, nerve or the physiological disorder of the method treatment to comprise: the needs that the memory that inhibitable type depression, memory deficiency, expection take place in the future increases, anxiety or with anxiety the very few obstacle of relevant disease, inappetence and feed such as apositia and polyphagia, stress be expected at take place in the future stress, stress disorders and because the motivation shortage that study or memory problems cause after the wound.In a desirable embodiment of the present invention, the downward modulation of CRF system is to having produced the treatment benefit with the positively related bad spirit of CRF receptor, nerve or physiological disorder.

Can be used for improving individual processing should be in the ability of the stressful situation that occurs in the future intermittently to use CRF receptor stimulating agent (have or do not have and intermittently use μ and/or delta opiate receptor antagonist).This is illustrating by the following fact: in fact stress be useful to live body a spot of intermittence.The suitable adaptation of a small amount of stress stimulation at intermittence like this makes organism can handle the stressful situation that occurs in the future better.Intermittently stress in fact cause increase the intermittence of cortisol levels.It also is that use CRF intermittence and/or the AVP agonist takes place that such cortisol levels intermittently increases.Therefore intermittently use the CRF receptor stimulating agent simulate a spot of intermittence stress the time taken place.It in the recent period temporary transient basis, induce in the individuality physiological stress (physiogical stress) (promptly, CRF discharges increase), it is enough little ' stress ' and the persistent period enough short make its can not occur chronic greatly stress the time side reaction (, ergogenic CRF and/or AVP system) that can occur.This method is intended to make individuality can handle better in more greatly stress of occurring in the future.In other words, stand a small amount of intermittently stress live body (promptly, the temporary transient CRF level that increases) will with never stand such short-term temporarily stress organism compare handle better in the future a large amount of stress (that is, the significantly increase of CRF level), when such situation produces.When rapid stressful situation produced, desirable was, can with use the second relevant time durations at every turn in use CRF receptor antagonist and/or AVP receptor antagonist.

In another embodiment of the invention, the neurotransmitter system is the CRF system, and it comprises corticotropin-releasing factor as neurotransmitter, and the receptor of described type is the CRF receptor, part is the rise that CRF receptor antagonist and counter adaptation cause the CRF system.Regulating the CRF system via counter adaptation submits to and is entitled as in the U.S. Provisional Patent Application serial number 60/777,190 of " METHOD OF REGULATING THECRF AND AVP SYSTEMS BY INDUCING COUNTERADAPTATIONS " on February 27th, 2006 and describe.

Counter adaptation can be corticotropin-releasing factor to be increased by hypothalamic biosynthesis or release; The number of the binding site on the number of CRF receptor and/or the CRF receptor increases; Described receptor pair increases with CRF receptor stimulating agent and/or the bonded sensitivity of corticotropin-releasing factor; Or their any combination.

Appropriate C RF antagonist is above being described.The predose of CRF receptor antagonist desirably for enough height inducing the counter adaptation effect, but be not so high so that the patient produces intolerable direct effect.For example, predose can be about 0.1 to 100 μ g/kg/ days predose and 100 to 1000 μ g/kg/ days, continues 8 hours slow release.In some embodiments of the present invention, the predose of CRF receptor antagonist is about 1 to 50 μ g/kg/ days predose and 20 to 50 μ g/kg/ days, continues 8 hours slow release.

Desirably, neither use the CRF receptor stimulating agent in during the very first time relevant, also do not use the AVP receptor stimulating agent with use the CRF receptor antagonist at every turn.Yet in some embodiments of the present invention, CRF receptor stimulating agent and/or AVP receptor stimulating agent are used in one or more second time durations relevant with use the CRF receptor antagonist at every turn.Appropriate C RF receptor stimulating agent and AVP receptor stimulating agent and benefit thereof are above being described.

In another embodiment of the invention, μ and/or delta opiate receptor antagonist and CRF antagonist combination are used in during the very first time, its use half life and use between during ratio be not more than 1/2.The application process of μ and/or delta opiate receptor antagonist is above being described.

Use according to the CRF antagonist of these embodiments of the present invention and can be used for treating bad spirit, nerve or physiological disorder among the patient, described bad spirit, nerve or physiological disorder and CRF receptor negative correlation.Also can use the example of bad spirit, nerve or the physiological disorder of the method treatment to comprise with CRF receptor negative correlation, for example, atypical depression, weight increase or disease of eating too much at one meal, drowsiness and tired.In a desirable embodiment of the present invention, the rise of CRF system has produced the treatment benefit to bad spirit, nerve or the physiological disorder with CRF receptor negative correlation.

The AVP system

AVP is a hormone, is also referred to as ADH (vassopressin (antidiuretic hormone)), and it is the nonapeptide (Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly) with the circulus that forms by the disulfide bond between two cysteine residues.AVP is an active hormones, and it is originally synthetic as long 164 amino acid whose propetide ppAVP.Biologically-active moiety is AVP (20-28).The AVP nonapeptide further is decomposed into littler bioactive fragment in some cases, that is, and and AVP (4-9), AVP (4-8), AVP (5-9), AVP5-8).These littler fragments lack periphery hormonal activity (peripheral endocrineactivity), but show the selection activity in the CNS really.

The AVP hormone is produced by hypothalamus, just like CRF (and several other releasing factor).Yet AVP produces by being different from the body secretion that produces releasing factor such as CRF (it flows directly to anterior pituitary).Posthypophysis (posterior pituitary gland) is actually hypothalamic extension (extension).The cyton that produces AVP is in hypothalamus.AVP is transported to the AT (axonal terminal) of these neuron cell bodies from cyton, and it is positioned at pituitrin (posterior pituitary).AVP is released into circulation by pituitrin.

In circulation, AVP has two kinds of basic roles, peripheral action and central actions.Peripheral action is relevant with vasoconstriction, glycogen metabolism and diuresis.Central action and learning and memory, social behavior, thermal conditioning (thermoreguloation), autonomic function are relevant with emotion.

AVP and CRF synergism discharge from antepituitary to stimulate ACTH.AVP also has direct effect for the adrenal gland who is used to discharge hydrocortisone (adrenal).AVP has with CRF for the β endorphins and similarly acts on, and its stimulates β endorphins to discharge from anterior pituitary.

AVP stress in, and in depressed and anxiety, work thus.Relevant with ergogenic CRF system just like some dysthymic disorders (that is, depression and anxiety), depressed and anxiety are also relevant with ergogenic AVP system.Function of proof is in the AVP of V1b receptor antagonist early stage useful result as potential antidepressants and antianxiety drug in zooscopy.In addition, the antagonist that acts on the V1a receptor also can play the effect as antidepressants and antianxiety drugs.

Therefore, in one embodiment of the invention, the neurotransmitter system is the AVP system, it comprises that corticotropin-releasing factor is as neurotransmitter, the receptor of described type is the AVP receptor, and part is the AVP receptor stimulating agent, and counter adaptation causes the downward modulation of AVP system.Regulating the AVP system via counter adaptation submits to and is entitled as in the U.S. Provisional Patent Application serial number 60/777,190 of " METHOD OF REGULATING THECRF AND AVP SYSTEMS BY INDUCING COUNTERADAPTATIONS " on February 27th, 2006 and describe.

The AVP receptor can be, for example, and V1R (being also referred to as V1a), V2R or V3R (being also referred to as V1b).V3R is the major receptors in the hypophysis.V1R mainly is present in liver and the brain, and V2R mainly is present in kidney.In a desirable embodiment of the present invention, the AVP receptor is V1R receptor or V3R receptor.

Counter adaptation can be arginine vasopressin to be reduced by hypothalamic biosynthesis or release; The decreased number of the binding site on the number of AVP receptor and/or the AVP receptor; Described receptor pair reduces with AVP receptor stimulating agent and/or the bonded sensitivity of arginine vasopressin; Or their any combination.

Multiple chemical compound can be used as the AVP receptor stimulating agent.For example, many chemical compounds based on peptide are AVP receptor stimulating agents.Peptide can be synthetic or from mammal source, as cattle or pig or other.Peptide can be linearity or cyclic.Suitable peptide AVP agonist comprises, for example, felypressin (2-L-Phe-8-L-lys AVP), Desmopressin (1-(30 mercaptopropionic acid)-8-D-AVP) and any peptide analogues with AVP peptide (Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly) of AVP agonist activity.The AVP peptide agonists can further comprise any preceding peptide molecule, and it is cut into active AVP agonist by enzyme.The AVP peptide agonists can further comprise any chemical compound of the less bioactive fragment (as AVP (4-9), AVP (4-8), AVP (5-9), AVP (5-8)) that contains the AVP nonapeptide.Be applicable to that other AVP receptor stimulating agent of the present invention is included in United States Patent (USP) 6,090,803; 6,096,735; 6,096,736; 6,194,407; 6,235,900; 6,268,360; 6,297,234; 6,335,327; 6,344,451; 6,620,807; 6,642,223; With 6,831, those disclosed in 079, its every piece document is incorporated this paper by reference into.As understood as technical staff, the pharmaceutically useful salt of above-mentioned AVP agonist or derivant also can be used for method of the present invention.

The predose of AVP receptor stimulating agent desirably for enough height inducing the counter adaptation effect, but be not so high so that the patient produces intolerable direct effect.For example, predose can be about 0.1 to 100 μ g/kg/ days predose and 100 to 1000 μ g/kg/ days, continues 8 hours slow release.In some embodiments of the present invention, the predose of AVP receptor stimulating agent is about 1 to 50 μ g/kg/ days predose and 20 to 50 μ g/kg/ days, continues 8 hours slow release.

Desirably, neither use the CRF receptor antagonist in during the very first time relevant, also do not use the AVP receptor antagonist with use the CRF receptor stimulating agent at every turn.Yet in some embodiments of the present invention, CRF receptor antagonist and/or AVP receptor antagonist are used in one or more second time durations relevant with use the CRF receptor stimulating agent at every turn.CRF receptor antagonist and AVP receptor antagonist are above being described.

In another embodiment of the invention, μ and/or delta opiate receptor antagonist and AVP agonist is co-administered in during the very first time, its use half life and use between during ratio be not more than 1/2.The application process of μ and/or delta opiate receptor antagonist is above being described.This can be desirable due to the fact that: the use of AVP agonist though be intended to cause the downward modulation of AVP system, can have also with the unintentional result of β endorphins from the release downward modulation of anterior pituitary.Such endorphins discharges and reduces the required reverse effect of bad disease (as depression and anxiety disorder) that will cause with the horizontal reverse correlation of improvement and circulation endorphins.The repetitive administration opiate antagonist can have two kinds of important effects: blocking-up is by the downward modulation of the endorphins of AVP agonist, causes the rise of aforesaid endorphins system in addition.It is as indicated above with the principle of inducing endogenous endorphins system to raise to use opiate antagonist.As mentioned above, desirable is to use CRF and/or AVP antagonist in second time durations relevant with use the AVP agonist at every turn.Desirably, with use the relevant very first time at every turn during in neither use the CRF receptor antagonist, do not use the AVP receptor antagonist yet.

Use according to the AVP agonist of this embodiment of the present invention and can be used for treating bad spirit, nerve or physiological disorder among the patient, described bad spirit, nerve or physiological disorder and AVP receptor positive correlation.With AVP receptor positive correlation and can use the example of bad spirit, nerve or the physiological disorder of the method treatment to comprise: the needs that the memory that inhibitable type depression, memory deficiency, expection take place in the future increases, anxiety or with anxiety the very few obstacle of relevant disease, inappetence and feed such as apositia and polyphagia, stress be expected at take place in the future stress, stress disorders and because the motivation shortage that study or memory problems cause after the wound.In a desirable embodiment of the present invention, the downward modulation of AVP system is to having produced the treatment benefit with the positively related bad spirit of AVP receptor, nerve or physiological disorder.

Can be used for improving individual processing should be in the ability of the stressful situation that occurs in the future intermittently to use AVP receptor stimulating agent (have or do not have and intermittently use μ and/or delta opiate receptor antagonist).This is illustrating by the following fact: in fact stress be useful to live body a spot of intermittence.The suitable adaptation of a small amount of stress stimulation at intermittence like this makes organism can handle the stressful situation that occurs in the future better.Intermittently stress in fact cause increase the intermittence of cortisol levels.It also is to take place when intermittently using the AVP receptor stimulating agent that such cortisol levels intermittently increases.Therefore intermittently use the AVP receptor stimulating agent simulate a spot of intermittence stress the time taken place.It in the recent period temporary transient basis, induce in the individuality physiological stress (promptly, AVP discharges increase), it is enough little ' stress ' and the persistent period enough short make its can not occur chronic greatly stress the time side reaction (, ergogenic CRF and/or AVP system) that can occur.This method is intended to make individuality can handle better in more greatly stress of occurring in the future.In other words, stand a small amount of intermittently stress live body (promptly, the temporary transient AVP level that increases) will with never stand such short-term temporarily stress organism compare handle better in the future a large amount of stress (that is, the significantly increase of CRF level), when such situation produces.When rapid stressful situation produced, desirable was, can with use the second relevant time durations at every turn in use CRF receptor antagonist and/or AVP receptor antagonist.

In another embodiment of the invention, the neurotransmitter system is the AVP system, and it comprises corticotropin-releasing factor as neurotransmitter, and the receptor of described type is the AVP receptor, part is the rise that AVP receptor antagonist and counter adaptation cause the AVP system.Regulating the AVP system via counter adaptation submits to and is entitled as in the U.S. Provisional Patent Application serial number 60/777,190 of " METHOD OF REGULATING THECRF AND AVP SYSTEMS BY INDUCING COUNTERADAPTATIONS " on February 27th, 2006 and describe.

Counter adaptation can be corticotropin-releasing factor to be increased by hypothalamic biosynthesis or release; The number of the binding site on the number of AVP receptor and/or the AVP receptor increases; Described receptor pair increases with AVP receptor stimulating agent and/or the bonded sensitivity of arginine vasopressin; Or their any combination.

Proper A VP antagonist is above being described.The predose of AVP receptor antagonist desirably for enough height inducing the counter adaptation effect, but be not so high so that the patient produces intolerable direct effect.For example, predose can be about 0.1 to 100 μ g/kg/ days predose and 100 to 1000 μ g/kg/ days, continues 8 hours slow release.In some embodiments of the present invention, the predose of AVP receptor antagonist is about 1 to 50 μ g/kg/ days predose and 20 to 50 μ g/kg/ days, continues 8 hours slow release.

Desirably, neither use the CRF receptor stimulating agent in during the very first time relevant, also do not use the AVP receptor stimulating agent with use the AVP receptor antagonist at every turn.Yet in some embodiments of the present invention, CRF receptor stimulating agent and/or AVP receptor stimulating agent are used in one or more second time durations relevant with use the CRF receptor antagonist at every turn.Appropriate C RF receptor stimulating agent and AVP receptor stimulating agent are above being described.

Use according to the AVP antagonist of this embodiment of the present invention and can be used for treating bad spirit, nerve or physiological disorder among the patient, described bad spirit, nerve or physiological disorder and AVP receptor negative correlation.Also can use the example of bad spirit, nerve or the physiological disorder of the method treatment to comprise with AVP receptor negative correlation, for example, atypical depression, weight increase or disease of eating too much at one meal, drowsiness and tired.In a desirable embodiment of the present invention, the rise of AVP system has produced the treatment benefit to bad spirit, nerve or the physiological disorder with AVP receptor negative correlation.

In another embodiment of the invention, μ and/or delta opiate receptor antagonist and AVP antagonist combination are used in during the very first time, its use half life and use between during ratio be not more than 1/2.The application process of μ and/or delta opiate receptor antagonist is above being described.

The disease that immune system is relevant

Method of the present invention is used for the treatment of and/or handles immune system-relevant disease, the acceptor type of itself and neurotransmitter system receptor related.In these methods, immune system is raised.Can use method of the present invention handle or the immune system of treatment-example of relevant disease comprises: cancer, particularly have a cancer of the cancerous cell of essentially no ζ receptor; Autoimmune disease, innate immunity defective, because immunodeficiency and the acquired immunodeficiency that immunosuppressant treatment causes.The example of concrete autoimmune disease comprises: rheumatoid arthritis (rheumatoid arthritis), multiple sclerosis (multiple sclerosis), systemic lupus erythematosus (systemic lupus erythematosus), Addison's disease (Addison ' s disease), ALS (Lou GehrigShi disease (Lou Gehrig ' s Disease)), Alzheimer (Alzheimer ' s Disease), ankylosing spondylitis (Ankylosing Spondylitis), autism spectrum disorder (Autism Spectrum Disorders), autoimmune hemolytic anemia (Autoimmune Hemolytic Anemia), autoimmune progesterone dermatitis (AutoimmuneProgesterone Dermatitis), Behcet (Behcet ' s Disease), celiac disease (CeliacDisease), chronic fatigue syndrome (Chronic Fatigue Syndrome), Qiu-Shi syndrome (Churg-Strauss) (allergic granulomatosis (allergic granulomatosis)), CREST syndrome (CREST syndrome), clone disease (Crohn ' s Disease), dermatomyositis (Dermatomyositis), diabetes (Diabetes Mellitus), emphysema (Emphysema) (COPD), endometriosis (Endometriosis), fibromyalgia (Fibromyalgia), Gourde(G) Paasche Che Shi disease (Goodpasture ' sdisease), Graves disease (Graves disease), chronic lymphocytic thyroiditis (Hashimoto ' s thyroiditis), between the granulomatous dermatitis of matter (Interstitial Granulomatous Dermatitis), irritable bowel syndrome (Irritable Bowel Syndrome) (IBS), mixed connective tissue disease (Mixed ConnectiveTissue Disease), the connective tissue disease relevant (autoimmune-relatedconnective tissue disorders) with autoimmune, myasthenia gravis (Myasthenia Gravis), parkinson (Parkinson ' s Disease), pemphigoid (Pemphigoid), pernicious anemia (Pernicious Anemia), primary lateral sclerosis (Primary Lateral Sclerosis) (PLS), polychondritis (Polychondritis) (recurrent), polymyalgia rheumatica (Polymyalgia Rheumatica), polymyositis (Polymyositis), psoriasis (Psoriasis), sarcoidosis (Sarcoidosis), scleroderma (Scleroderma), siogren's syndrome (Sjogren ' s syndrome), transverse myelitis (Transverse Myelitis), ulcerative colitis (Ulcerative Colitis), vasculitis (Vasculitis), Wei Genashi granulomatosis (Wegener ' sGranulomatosis) and be secondary to course of infection, use autoimmune disease (the autoimmune disorders secondary to infectious processes of vaccine or environment reaction, administration ofvaccines or environmental reactions) (for example, is secondary to chemicals such as silicones (silicones)).According to one embodiment of the invention, the probability of the infected property of the disease infected by microbes by this method treatment.Described microorganism such as antibacterial, virus, fungus, parasite, Mycobacterium, yeast, chlamydiaceae, protozoacide (protazon), anthelmintic (helminth) or rickettsia (rickettsia) or virus, for example, HIV, influenza virus (influenza) hepatitis virus (hepatitis) (first type, B-mode, third type), respiratory syncytial virus (respiratory syncitial virus) (RSV), gastrointestinal viral infection (gastrointestinal viral infections), encephalitis (encephalitis) and myocarditis (myocarditis).According to another embodiment of the invention, immune system-associated conditions is using of vaccine, and immune rise causes production of antibodies to increase, and described antibody is at the material of described vaccine institute targeting.

In desirable especially embodiment of the present invention, the neurotransmitter system is that endogenous endorphins system and described acceptor type are delta opiate receptors, its usually with bad immune system-relevant disease negative correlation.Part is a delta opiate receptor antagonist, and counter adaptation causes immune rise.Can be used in this embodiment of the present invention at above-described any delta opiate receptor antagonist.In some embodiments of the present invention, delta opiate receptor antagonist is not naltrexone or naloxone.In desirable embodiments more of the present invention, the predose of delta opiate receptor antagonist is used greater than 10mg/; Use greater than 10.5mg/; Use greater than 11mg/; Or even use greater than 15mg/.The δ receptor antagonist desirably is a δ receptor-selective antagonist; It desirably has the activity less basically with respect to the μ receptor.An example of suitable δ receptor antagonist has following structure:

As above described about emotion, can there be the decline of function of immune system in during the very first time relevant with use part at every turn.In addition, if implementation of class is similar to the described method according to Fig. 6, then in the initial period of successive administration, can there be the decline of function of immune system.Therefore, desirable is, can these the time interim one or more additional medicines of using.For example, desirable is, can be during the very first time in and/or part administration continuously the time interim with autoimmunity medicine and ligand united using.The example of suitable autoimmune treatment comprises medicine such as corticosteroid (corticosteroids), chlorambucil (chlorambucil), ciclosporin (cyclosporine), cyclophosphamide (cyclophosphamide), methotrexate (methotrexatate), azathioprine (azathioprine), TNF alpha-2 antagonists, and treatment, as systemic enzyme treatment, gene therapy, radiotherapy.Certainly, recognize that other autoimmune medicine can be used for method of the present invention, comprise those of exploitation in the future as the technical staff.In some embodiments of the present invention, in second time durations, do not use the autoimmune treatment.

Similarly, desirable is, can be during the very first time in and/or part administration continuously the time interim with antiviral agent and ligand united using.Suitable antiviral agent example comprises interferon (interferon), ribavirin (ribavirin), protease inhibitor (protease inhibitors), amantadine (amantadine), rimantadine (rimantadine), pleconaril (pleconaril), antibody (monoclonal, anti--VAP, receptor resists-idiotype (receptor anti-idiotypic), external receptor and synthesis of receptor analogies), acycloguanosine (acyclovir), zidovudine (zidovudine) (AZT), lamivudine (lamivudine), RNAase H inhibitor, integrase inhibitor, the attached blocking-up thing of transcription factor and viral DNA, so-called ' antisense ' molecule, synthetic ribozyme (synthetic ribozymes), zanamivir (zanamivir) and oseltamivir (osletamivir).Certainly, recognize that other antiviral drugs can be used for method of the present invention, comprise those of exploitation in the future as the technical staff.In some embodiments of the present invention, in second time durations, do not use antiviral agent.

Similarly, desirable is, can be during the very first time in and/or part administration continuously the time interim with antimicrobial, antifungal and/or antitumor agent and ligand united using.In some embodiments of the present invention, in second time durations, do not use antimicrobial, antifungal and/or antitumor agent.

Desirable is, can be during the very first time in and/or part administration continuously the time interim with anticarcinogen and ligand united using.Suitable anticarcinogen comprises; for example; amycin (adriamycin); busulfan (busulfan); carboplatin (carboplatin); chlorambucil; cisplatin (cisplatin); cyclophosphamide; ifosfamide (ifosfamide); chlormethine (mechlorethamine); melphalan (melphalan); procarbazine (procarbazine); temozolomide (temozolamide); daunorubicin (daunorubicin); doxorubicin (doxorubicin); idarubicin (idarubicin); bleomycin (bleomycin); mitomycin (mitomycin); mitoxantrone (mitoxantrone); plicamycin (plicamycin); cytosine arabinoside (cytarabine); fluorouracil (fluorouracil); hydroxyurea (hydroxyurea); methotrexate; asparaginase (asparaginase); pegaspargase (pegaspargase); irinotecan (irinotecan); hycamtin (topotecan); bicalutamide (bicalutamide); estramustine (estramustine); flutamide (flutamide); leuprorelin (leuprolide); megestrol (megestrol); nilutamide (nilutamide); testosterone (testosterone); triptorelin (triptorelin); Anastrozole (anastrazole); letrozole (letrozole); aldesleukin (aldesleukin); alemtuzumab (alemtuzumab); gemtuzumab (gemtuzumab); toremifene (toremifene); trastuzumab (trastuzumab); etoposide (etoposide); Docetaxel (docetaxel); paclitaxel (paclitaxel); vinblastine (vinblastine); vincristine (vincristine); vinorelbine (vinorelbine); altretamine (altretamine); erlotinib; gleevec; Rhizoma Curcumae Longae (curcumin); tamoxifen (tamoxifen); bortezomib; gefitinib; imatinib (imatinib); be derived from 3; 4-methylene-dioxy-5; 4 '-dimethoxy-3 '-amino-Z-stilbene (3; 4-methylenedioxy-5,4 '-the growth of cancer cells inhibitor of dimethoxy-3 '-amino-Z-stilbene); his fourth (hydroxyphenstatin) and dibastic sodium phosphate prodrug (sodium diphosphate prodrug) thereof of oxybenzene; histone deacetylase inhibitors (histone deacetylaseinhibitors); octanedioyl aniline hydroxamic acid (suberoylanilide hydroxamic acid); Trichostatin A (trichostatin A); sodium butyrate (sodium butyrate); metformin (metformin); five-lipoxidase (5-LO) antagonist (five-lipoxygenase antagonist); the antisense oligonucleotide of the RI α regulator subunit of targeting I type protein kinase A (antisense oligonucleotides targeting theRI α regulatory subunit of protein kinase A type I); vitamin E and analog thereof; tocopherol acid succinate (VES) and gene therapy.Certainly, recognize that other anticarcinogen can be used for method of the present invention, comprise those of exploitation in the future as the technical staff.In some embodiments of the present invention, in second time durations, do not use antiviral agent.

Cancer is a kind of bad Ia disease, and it can use method treatment as herein described and/or handle.In a desirable embodiment of the present invention, thereby by using repetitive administration delta opiate receptor antagonist as indicated above to transfer to realize that immune rise is handled or the treatment cancer in the endogenous endorphins system.Cancerous cell and immunocyte (that is killer cell (killer cells)) all have opiate receptor.When immune system stands timing, give the ability of killer cell enhanced ' attack ' cancerous cell.Other benefit is to make the cancerous cell pair cell death of rise responsive more.Desirably, use according to the described method of Fig. 6, the successive administration that wherein carries out part earlier raises in mode faster with the induction of immunity system.The seriousness that depends on cancer, the time of this successive administration can be, for example, from one day to several weeks or several months.

Except that only blocking the enhanced cancer cell multiplication, there is the advantage of the increase that opiate antagonist and anticarcinogen use simultaneously by anticarcinogen.Because cancerous cell is induced with growth quickly, therefore make them responsive more to the effect of anticarcinogen.Thereby can have enhanced toxic action to cancerous cell at the anticarcinogen during this period of time of cancerous cell fast breeding.Prepare anticarcinogen in this way with more effective aspect the inducing cancer cell death.

Method of the present invention also can be used for handling and/or treatment immune disorders and infectious disease.In a desirable embodiment of the present invention, thereby by using repetitive administration delta opiate receptor antagonist as indicated above to transfer to realize that immune rise is handled or the treatment cancer in the endogenous endorphins system.To be similar to the mode that starts treatment of cancer, can select continuous receptor blocking begin treatment with short-term, as top according to as described in Fig. 6.

For, for example, the reaction of the counter adaptation of opium antagonism is immune rise.The immune system that raises causes the enhanced immunoreation by immunocyte such as killer cell and other immunocyte.The immune system of such rise can be used for treating the disease with abnormal immune system.These immune disorders can be selected from, but are not limited to, autoimmune disease, innate immunity defective, because immunodeficiency that immunosuppressant treatment (that is, being used for cancer, transplanting) causes or acquired immunodeficiency are (that is, AIDS).The immune system that raises can have other benefit, and it resists the ability that (fight off) infects for being intended to strengthen health, and described infection comprises antibacterial and viral infection, and from those infection of other infective micro-organisms.

Autoimmune disease is to have parafunctional immune those diseases, and wherein the tissue at health oneself produces immunoreation.Because being immune system, autoimmune disease raises (turn up) its active result at normal cell and cellular component, therefore seem, if immune system is enhanced, then it is owing to should make these disease progressions at the increased activity of the tissue of intrasubject.Shown that the autoimmune systemic disease is advantageously in response to enhanced immune system antithesis.

One embodiment of the invention relate to the high relatively dosage of use (promptly, be equivalent to greater than 10mg naloxone or naltrexone, it further comprises many analog) the δ opiate antagonist be used for even the rise of strong relatively endogenous endorphins system, raise immune system thus relatively doughtily.

For a lot of infection,, there is the initial period of continuous receptor blocking in the described method when implementing to realize the another kind of benefit that increases with according to described those the similar methods of Fig. 6 the time.For example, during viral infection, interimly when this section of receptor blocking there is virion because immune inhibition and enhanced propagation.Can utilize this point by using the agent that kills or suppress the virus in the reproduction process.Because virion is (pace) propagation at faster speed, so they can become to suppressing their growths and causing the agent of their death responsive more.Make that like this antiviral agent is more effective, because it attacks the virus in the reproduction process, this moment, described virus was pregnable.Other benefit is after the phase, to have the immune system that raises at continuous receptor blocking, and wherein immunocyte is more effective aspect the virion that destroys any remnants.These antiviral agent of following can be selected from down group: interferon, ribavirin, in the multiple protein enzyme inhibitor any, amantadine, rimantadine, pleconaril, antibody (monoclonal, anti--VAP, receptor resists-idiotype, external receptor and synthesis of receptor analogies), acycloguanosine, zidovudine (AZT), lamivudine, RNAase H inhibitor, integrase inhibitor, the attached blocking-up thing of transcription factor and viral DNA, ' antisense ' molecule, synthetic ribozyme, zanamivir

And oseltamivir (Tamiflu (oseltamivir phosphate capsule)

).Certainly, as understood as technical staff, can use any suitable antiviral drugs.

The mode that can prevent is used method of the present invention, that is, and and to reduce the probability of microorganism of infected property or viral infection.For example, can be before operation (operation) be with the risk that reduce to infect, carry out method of the present invention after the operating process neutralization.In fact method of the present invention can be used as at the preventive measure of any infectious agent, described infectious agent such as HIV, hepatitis, influenza, RSV, tuberculosis, protozoacide, rickettsia, malaria and staphylococcus (staphylococcus).

Other disease

According to a further aspect in the invention, be used for the treatment of or dispose cardiovascular disorder or the disease relevant in above-described method, as cardiovascular disorder (for example, heart disease, peripheral blood vessel and apoplexy (stroke)) with lipid or cholesterol metabolism.Method of the present invention also is used for handling or treatment diabetes (for example, I type and II type).

It is predisposing to CV and diabetes that the disease of lipid or cholesterol metabolism is generally.Can use method treatment of the present invention or the lipid of disposing or the relevant disease of cholesterol metabolism to comprise hypertriglyceridemia (hypertriglyceridemia), hypercholesterolemia (hypercholesterolemia) (comprise the generally rising of cholesterol and/or the rising of low-density lipoprotein cholesterol [LDL], perhaps high density lipoprotein [HDL] cholesterol is low-level unusually).The disease of lipid metabolism also comprises because HIV (AIDS virus) infects the lipodystrophy (lipodystrophies) that causes.

As mentioned above, AVP neurotransmitter system relate to stress, ACTH/ hydrocortisone approach and emotional conditions such as depression and anxiety.Different and very concrete stress type be called ' nutrient stress (nutrientstress) '.The stressful situation that takes place when nutrient stress is fasting, hunger or insulin-inductive hypoglycemia (hypoglycemia).Nutrient stress causes glucocorticoid (glucocorticoid) level (hydrocortisone) that raises.Yet, with classics stress be different, CRF discharges and plays a major role in the nutrient stress hydrocortisone discharges.Yet AVP is the main instrumentality that the hydrocortisone of response nutrient stress discharges.

When discussion related to the factor that prolongs life, nutrient stress was crucial.Found before 70 years that thermal limit (caloric restriction) (it induces nutrient stress) can prolong the life of organism about 30%.After this proved that this phenomenon also is present in multiple mammal, comprised rat, mice, Canis familiaris L. and possible primates (primate).In fact, thermal limit is the unique method that has confirmed to increase the organism life-span.

It is believed that thermal limit works by activating the gene (it is called SIRT1 in mammal) that is called SIR2 in yeast.SIRT1 gene encoding enzyme Sirt1, its targeting control described critical process such as apoptosis (cell death), cytophylaxis (cell defense) and metabolic protein.Thereby think that Sirt1 stress activatedly be used for the main control thing of old and feeble regulating system.

For example, Sirt1 is the center metabolism instrumentality in liver, muscle and the adipose cell.This explanation Sirt1 relates to depot fat, and it is with old and feeble relevant with metabolic disease (as type 2 diabetes mellitus) like this.Another critical process of being modified by Sirt1 is inflammation.Known thermal limit suppresses over-drastic inflammation, and it is relevant with neural degeneration (neurodegeneration) with aging course such as heart disease.Sirt1 also regulates the generation of IGF-1 (insulin-like growth factor).The life-span of known IGF-1 control (dictate) multiple organism-worm, fly class, mice and possible philtrum.

The active chemical compound that to regulate Sir2 and its human relationship thing (human cousins) jointly is called ' Sirtuins (Sir2 sample protein) '.The Sirtuin-activated compounds can be abbreviated as ' STAC '.A kind of such STAC is reservatrol.Its usually red wine neutralization be subjected to stress the time various plants in find.In fact, some beneficial effects for health from red wine are considered to owing to reservatrol and/or other STACs.A lot of other (at least 18 kinds) chemical compounds are arranged, and it is in response to regulating stress producing by plant of sirtuins.

One aspect of the present invention relates to method, wherein imitates the physiology control mechanism that produced by thermal limit to cause the activation of Sirt1 approach.Any method of the present invention causes putting on intermittence of patient stress; Therefore, any method of the present invention can be used for activating the Sirt1 approach, and processing or the treatment bad disease relevant with the Sirt1 approach thus, as with aging, lipid metabolism, disease that inflammation is relevant with the IGF-1 system.Such disease comprises, for example, and cancer, arthritis, asthma, heart disease and neural degeneration.Method of the present invention also can be used as the preventive measure at the physiological change that is caused by aging.The technical staff can use any above-mentioned neurotransmitter system to activate the Sirt1 approach.

Thermal limit is a kind of inductive mode, is referred to as ' instinct (hormetic) ' effect, or stimulation (hormesis).1904, Starling design word ＂ hormone ＂ delivers to influence any material of some other organs in blood with a small amount of generation then with expression.It is from Greek ＂ Hormo ＂, and the meaning is that ＂ stimulates (To excite) ".Southam and Erlich find that the oak bark extract (oak barkextract) of high concentration suppresses conk, but its low dosage stimulates conk (Phytopathology33:517,1943).They are revised as ＂ stimulation (Hormesis) ＂ with the word of Starling, and it describes the notion of " low dose of toxin can be helpful ".Stimulation further is summarised as finger term gentle, the multiple long-term benefit that stress or stimulate.

One of stimulation is characterised in that it can be activated after certain stimulates.Shown that gentle stress to coerce (nutritional stress) as the external temperature that increases, gentle radioactive exposure (radiation exposure) or overweight (hypergravity) and nutrition (be thermal limit, [Frame, L.T., Deng, " Caloric Restriction as a Mechanism Mediating Resistance to EnvironmentalDisease ", Environ Health Perspect, 1998,106 (Suppl1): 303-324] all improve and old and feeble relevant series of parameters.Because thermal limit is not easy to obtain, so there is the driving force of the chemical compound of the effect of developing the simulation thermal limit.These chemical compounds are called ' thermal limit analogies (caloric restrictionmimetics) ' (Weindruch, R., Deng, " Caloric Restriction Mimetics-MetabolicInterventions ", Journals of Gerontology Series A:Biological Sciences and MedicalSciences, 2001,56:20-33.).

Therefore, not only induce the thermal limit of physiological parameter to improve relevant disease of age.Stress also can induce the physiological parameter as defense mechanism the intermittence of any low degree.Aspect this, stress be useful the intermittence of any gentleness for organism, because it induces the physiological parameter that gives its improved host defense mechanism.

According to an aspect of the present invention, the administration at intermittence (as described in above this paper) of neurotransmitter receptor part be used to induce gentle intermittence stress, it activates again in defense mechanism that stress time (for times of stress) protection organism.Use is in above-described method, and relevant with dysphoria (dysphoria) any neurotransmitter system can be used for simulating thermal limit.For example, stress disease relevant at above-described all neurotransmitter systems and dysphoria.Therefore, above-described all methods, neurotransmitter system and part can be used for inducing less instantaneous stress, and the effect that therefore can be used for inducing instinct effect (hormetic effect) and simulate thermal limit.In some embodiments of the present invention, these defense mechanisms are such mechanism, its stress the guardtime organism to improve the disease of aging, lipid metabolism, inflammation and IGF-1 system, as cancer, arthritis, asthma, heart disease and neural degeneration.

Exercise performance is relevant with a plurality of neurotransmitter systems (as endogenous endorphins system).Health produces endorphins in response to taking exercise.That the level of intensity level and athletic training and endorphins are replied is directly related (see Mougin, etc., Eur J App Physiol, 1988; Doiron, etc., J Str Cond Res, 1999; Sforzo, Sport Med, 1989: and Golbfarb, etc., Sport Med, 1997.).Because highly the high intensity level in Xun Lian athlete and the exercise is directly related with endorphins release, the endorphins system of rise can be useful for improving exercise performance.Therefore, one aspect of the present invention relates to the purposes that is used to improve this method, neurotransmitter system and the part of exercise performance above-described.In addition, can be of value to treatment of cancer, treatment infectious disease and autoimmune treatment just like the continuous receptor blocking of short-term, as mentioned above, the technical staff can use the continuous receptor blocking of short-term in training, for example according to Fig. 6.According to one embodiment of the invention, the neurotransmitter system is an endogenous endorphins system, and part is that μ and/or delta opiate receptor antagonist and counter adaptation are the rises of endogenous endorphins system.

Cognitive (cognition) (for example, learning and memory) also directly related with neurotransmitter system such as endogenous endorphins system (Riley, etc., Neurosci Biobehav Rev, 1980; Getsova, etc., NeurosciBehav Physiol, Biomed ﹠amp; Life Sci ﹠amp; Russian Library of Sci, 1986.).Sharply use delta opiate receptor antagonist (for example, naltrexone) and suppress learning and memory (Chaves, etc., Neuropsychologia, 1988).Contact between neurotransmitter system and the cognition further shows by the following fact: the level of glucocorticoid is relevant with cognitive function in the circulation; Continue high-caliber hydrocortisone relevant with impaired memory (Li, etc., Neurobio Aging, 2005).On the other hand, the instantaneous rising improvement learning and memory task of glucocorticoid (Patel, etc., Neurol Aging, 2002).Therefore, one aspect of the present invention relates to the purposes that is used to improve cognitive this method, neurotransmitter system and part above-described.For example, these methods can be used for only causing the instantaneous rising of glucocorticoid.The purposes of above-described any method, neurotransmitter system and part will cause less, intermittently stress, it causes the instantaneous of short duration rising of glucocorticoid again.Therefore, can be used for improving cognitive at above-described any method, neurotransmitter system and part.In another example, in order to improve cognition, the technical staff can use μ as indicated above and/or delta opiate receptor antagonist to realize the rise of interior origin system.In addition, continuous receptor blocking just like short-term can be of value to treatment of cancer, treatment infectious disease and autoimmune treatment, and as mentioned above, the technical staff can use the continuous receptor blocking of short-term, for example, as to produce cognitive function improvement faster according to Fig. 6.

It will be apparent to one skilled in the art that and to carry out various modifications and variation and without departing from the spirit and scope of the present invention to the present invention.Therefore, the invention is intended to contain modification of the present invention and change, as long as they are in the scope of claims and equivalent thereof.All lists of references of this paper citation are all incorporated into by reference in full at this.

Claims

1. by inducing counter adaptation to regulate the method for neurotransmitter system in the patient, described neurotransmitter system comprises acceptor type, and described method comprises:

The part repetitive administration of described acceptor type in described patient, is used at every turn and is had the half life of using, thus with use the relevant very first time at every turn during in make the receptors bind of described part and the type, induce thus, keep or improve counter adaptation,

Wherein said counter adaptation cause to the adjusting of neurotransmitter system and

Wherein use half life and use between during ratio be not more than 1/2.

2. the process of claim 1 wherein with described part repetitive administration before described patient, induce counter adaptation by the part that described patient is given described acceptor type, and with this part repetitive administration to keep or to improve described counter adaptation.

3. claim 1 or 2 method, wherein the adjusting to described neurotransmitter system has produced the treatment benefit to bad spirit, nerve or the physiological disorder relevant with described acceptor type.

4. each method among the claim 1-3, wherein said part is the receptor stimulating agent of described acceptor type, and described adjusting is the downward modulation of neurotransmitter system.

5. the method for claim 4, wherein bad spirit, nerve or physiological disorder and described acceptor type positive correlation.

6. each method among the claim 4-5, wherein said counter adaptation are at least a in the following situation:

With the biosynthesis of the neurotransmitter of the receptors bind of described acceptor type or discharge and reduce;

Increase with the absorption again of the neurotransmitter of the receptors bind of described acceptor type;

The decreased number of the binding site on the number of described acceptor type and/or the receptor of described acceptor type; With

The receptor of described acceptor type pair reduces with the bonded sensitivity of natural neurotransmitter and/or receptor stimulating agent.

7. each method among the claim 4-6, wherein with use the relevant very first time at every turn during in do not use the antagonist of the receptor of described acceptor type.

8. each method among the claim 4-7, wherein use at every turn and have relative second time durations, described second time durations with use the relevant very first time during after, and wherein in one or more described second time durations, use the antagonist of the receptor of described acceptor type.

9. each method among the claim 1-3, wherein said part is that the antagonist and the described adjusting of the receptor of described acceptor type is the rise of neurotransmitter system.

10. the method for claim 9, wherein bad spirit, nerve or physiological disorder and described acceptor type negative correlation.

11. the method for claim 9 or 10, wherein said counter adaptation are at least a of following situation:

With the biosynthesis of the neurotransmitter of the receptors bind of described acceptor type or discharge and increase;

Reduce with the absorption again of the neurotransmitter of the receptors bind of described acceptor type;

The number of the binding site on the number of described acceptor type and/or the receptor of described acceptor type increases; With

Described receptor pair improves with the bonded sensitivity of part and/or receptor stimulating agent.

12. each method among the claim 9-11, wherein with use the relevant very first time at every turn during in do not use the agonist of the receptor of described acceptor type.

13. each method among the claim 9-12, wherein use at every turn and have relative second time durations, described second time durations with use the relevant very first time during after, and wherein in one or more described second time durations, use the agonist of the receptor of described acceptor type.

14. each method among the claim 1-13, wherein the receptor of most described acceptor type combines with described part in during each very first time.

15. the method for claim 14 wherein combines with described part at least about in 30% receptor is during each very first time.

16. the method for claim 14 wherein combines with described part at least about in 50% receptor is during each very first time.

17. the method for claim 14 wherein combines with described part at least about in 75% receptor is during each very first time.

18. the method for claim 14 wherein combines with described part at least about in 90% receptor is during each very first time.

19. each method among the claim 1-18 wherein continues at least about 5 minutes during each very first time.

20. each method among the claim 1-18 wherein continues at least about 30 minutes during each very first time.

21. each method among the claim 1-18 wherein continues at least about 1 hour during each very first time.

22. each method among the claim 1-18 wherein continues at least about 2 hours during each very first time.

23. each method among the claim 1-18 wherein continues at least about 4 hours during each very first time.

24. each method among the claim 1-23 wherein continues to be less than about 24 hours during each very first time.

25. each method among the claim 1-23 wherein continues to be less than about 16 hours during each very first time.

26. each method among the claim 1-23 wherein continues to be less than about 12 hours during each very first time.

27. each method among the claim 1-23 wherein continues to be less than about 8 hours during each very first time.

28. each method among the claim 1-23 wherein continues to be less than about 6 hours during each very first time.

29. each method among the claim 1-28, wherein use at every turn and have relative second time durations, described second time durations with use the relevant very first time during after, and wherein among each second time durations most of receptor keep not combining with described part.

30. the method for claim 29 wherein is no more than about 50% receptor and combines with described part in each second time durations.

31. the method for claim 29 wherein is no more than about 25% receptor and combines with described part in each second time durations.

32. the method for claim 29 wherein is no more than about 10% receptor and combines with described part in each second time durations.

33. each method among claim 13-18 and the 29-32, wherein each second time durations continued at least about 2 hours.

34. each method among claim 13-18 and the 29-32, wherein each second time durations continued at least about 10 hours.

35. each method among claim 13-18 and the 29-32, wherein each second time durations continued at least about 15 hours.

36. each method among claim 13-18 and the 29-32, wherein each second time durations continues to be no more than about 20 hours.

37. each method among claim 13-18 and the 29-32, wherein each second time durations continues to be no more than about 30 hours.

38. each method among claim 13-18 and the 29-32, wherein each second time durations continues to be no more than about 50 hours.

39. each method among the claim 1-38, wherein use half life and use between during ratio be no more than 1/3.

40. each method among the claim 1-39, wherein part use half life and use between during ratio be no more than 1/5.

41. each method among the claim 1-39, wherein part use half life and use between during ratio be no more than 1/8.

42. each method among the claim 1-39, wherein part use half life and use between during ratio be no more than 1/12.

43. each method among the claim 1-42, wherein part use half life and use between during ratio be higher than 1/24.

44. each method among the claim 1-42, wherein part use half life and use between during ratio be higher than 1/12.

45. each method among the claim 1-42, wherein part use half life and use between during ratio be higher than 1/8.

46. each method among the claim 1-42, wherein part use half life and use between during ratio be higher than 1/5.

47. each method among the claim 1-42, wherein part use half life and use between during ratio be higher than 1/4.

48. each method among the claim 1-42, wherein part use half life and use between during ratio be higher than 1/3.

49. each method among the claim 1-48, the part dosage of wherein at every turn using increases in time.

50. each method among the claim 1-49, the part dosage of wherein using discontinuity in time increase at every turn.

51. the method for claim 50 is no less than a week during between wherein said dosage increases.

52. the method for claim 50 was no less than for two weeks during between wherein said dosage increases.

53. the method for claim 50 was no less than for three weeks during between wherein said dosage increases.

54. the method for claim 50 is no less than one month during between wherein said dosage increases.

55. the method for claim 50 is no less than two months during between wherein said dosage increases.

56. the method for claim 50 is no less than three months during between wherein said dosage increases.

57. the method for claim 50 is no less than six months during between wherein said dosage increases.

58. the method for claim 50 is no less than 1 year during between wherein said dosage increases.

59. each method among the claim 50-58, wherein in each increase of dosage, described dosage is with respect to predose increase at least 5%.

60. each method among the claim 50-58, wherein in each increase of dosage, described dosage is with respect to predose increase at least 10%.

61. each method among the claim 50-58, wherein in each increase of dosage, described dosage is with respect to predose increase at least 25%.

62. each method among the claim 50-58, wherein in each increase of dosage, described dosage is with respect to predose increase at least 50%.

63. each method among the claim 50-58, wherein in each increase of dosage, described dosage is with respect to predose increase at least 100%.

64. each method among the claim 50-63, wherein maximal dose is in 300 times of predose.

65. each method among the claim 50-63, wherein said maximal dose is in 100 times of predose.

66. each method among the claim 50-63, wherein said maximal dose is in 50 times of predose.

67. each method among the claim 50-63, wherein said maximal dose is in 20 times of predose.

68. each method among the claim 1-67, carry out the every day of using of wherein said part.

69. each method among the claim 1-68 is more than 2 days during between wherein said the using.

70. each method among the claim 1-68 is more than 3 days during between wherein said the using.

71. each method among the claim 1-68 is more than 5 days during between wherein said the using.

72. each method among the claim 1-68 is more than 1 week during between wherein said the using.

73. each method among the claim 1-68 is more than 2 weeks during between wherein said the using.

74. each method among the claim 1-68 is more than 1 month during between wherein said the using.

75. each method among the claim 1-74, the wherein said half life of using, be less than about 16 hours.

76. each method among the claim 1-74, the wherein said half life of using, be less than about 12 hours.

77. each method among the claim 1-74, the wherein said half life of using, be less than about 8 hours.

78. each method among the claim 1-74, the wherein said half life of using, be less than about 4 hours.

79. each method among the claim 1-78, the wherein said half life of using, be higher than about 4 hours.

80. each method among the claim 1-78, the wherein said half life of using, be higher than about 12 hours.

81. each method among the claim 1-78, the wherein said half life of using, be higher than about 16 hours.

82. each method among the claim 1-78, the wherein said half life of using, be higher than about 30 hours.

83. each method among the claim 1-82, the chemical compound half life of wherein said part, be less than about 16 hours.

84. each method among the claim 1-82, the chemical compound half life of wherein said part, be less than about 12 hours.

85. each method among the claim 1-82, the chemical compound half life of wherein said part, be less than about 8 hours.

86. each method among the claim 1-82, the chemical compound half life of wherein said part, be less than about 4 hours.

87. each method among the claim 1-86, the chemical compound half life of wherein said part, be higher than about 4 hours.

88. each method among the claim 1-86, the chemical compound half life of wherein said part, be higher than about 16 hours.

89. each method among the claim 1-86, the chemical compound half life of wherein said part, be higher than about 30 hours.

90. each method among the claim 1-86, the chemical compound half life of wherein said part, be higher than about 12 hours.

91. the method for claim 90, the chemical compound half life of wherein said part, be higher than about 12 hours, and wherein said method is further comprising the steps of

Repeat and with less than second part of using described acceptor type during every other day, the half life of using of at every turn using second part is less than about 8 hours.

92. the method for claim 91, wherein the chemical compound half life,, to be higher than about 12 hours part be agonist, and described second part is an agonist.

93. the method for claim 91, wherein the chemical compound half life,, to be higher than about 12 hours part be antagonist, and described second part is an antagonist.

94. each method among the claim 1-93, wherein said using repeated at least 5 times.

95. each method among the claim 1-93, wherein said using repeated at least 10 times.

96. each method among the claim 1-93, wherein said using repeated at least 25 times.

97. each method among the claim 1-93, wherein said using repeated at least 50 times.

98. each method among the claim 1-97, the dosage of wherein said part are enough to trigger counter adaptive reaction, make the bonded direct effect of ligand-receptor low and can tolerate for the patient but enough hang down.

99. each method among the claim 1-98, wherein the major part during the very first time occurs when the patient is in the sleep state.

100. each method among the claim 1-99, wherein at least 40% during the very first time occurs when the patient is in the sleep state.

Each method among the claim 1-99, wherein at least 60% during the very first time occurs when the patient is in the sleep state.

Each method among the claim 1-99, wherein at least 85% during the very first time occurs when the patient is in the sleep state.

Each method among the claim 1-102, at every turn being applied in patient a hour before going to bed of wherein said part carried out.

Each method among the claim 1-102, the patient that at every turn is applied in of wherein said part goes to bed and used in the past in last hour.

Each method among the claim 1-104, wherein said part use at every turn oral administration, transdermal, by suck, in subcutaneous, intravenous, intramuscular, spinal cord, in the sheath, saturating mucosa or use osmotic pumps, microcapsule, implant or suspension to carry out.

Each method among the claim 1-105, further comprising the steps of: with antianxiety drug and described ligand united using.

The method of claim 106, wherein said antianxiety drug influences the GABA approach.

The method of claim 106, wherein said antianxiety drug is a benzodiazepine

The class medicine.

The method of claim 108, wherein benzodiazepine

The class medicine is selected from down group: diazepam, lorazepam, alprazolam, temazepam, flurazepam and chlordiazepoxide.

110. each method among the claim 1-109 is further comprising the steps of:

With somnifacient and described ligand united using.

111. each method among the claim 1-110 is further comprising the steps of:

Described part is co-administered with the material that is selected from down group: TCA, MAOI, SSRI, NRI, SNRI, CRF regulator, 5-hydroxy tryptamine presynaptic autoreceptor antagonist, 5HT ₁Agonist, dynorphin antagonist, GABA-A regulator, 5-hydroxy tryptamine 5H _2CAnd/or 5H _2BRegulator, β-3 adrenoceptor agonists, nmda antagonist, V1B antagonist, GPCR regulator and P substance antagonist.

112. the method for claim 111, wherein said chemical compound is selected from down group: fluoxetine, Paroxetine, Sertraline, fluvoxamine, citalopram, escitalopram, venlafaxine and reboxetine.

113. each method also comprises the steps among the claim 1-112

During the very first time autoimmune is treated and described ligand united using.

114. the method for claim 113, wherein said autoimmune treatment is selected from down group: corticosteroid, chlorambucil, ciclosporin, cyclophosphamide, methotrexate, azathioprine, TNF alpha-2 antagonists, systemic enzyme treatment, gene therapy, radiotherapy.

115. the method for claim 113 is not wherein used the autoimmune medicine in second time durations.

116. each method also comprises the steps among the claim 1-112

During the very first time with antiviral agent and described ligand united using.

117. the method for claim 116, wherein antiviral agent is selected from down group: interferon, ribavirin, protease inhibitor, amantadine, rimantadine, pleconaril, antibody (monoclonal, anti--VAP, receptor is anti--idiotype, external receptor and synthesis of receptor analogies), attached blocking-up thing, antisense molecule, synthetic ribozyme, zanamivir and the oseltamivir of acycloguanosine, zidovudine (AZT), lamivudine, RNAase H inhibitor, integrase inhibitor, transcription factor and viral DNA.

118. the method for claim 116 is not wherein used described autoimmune medicine in second time durations.

119. each method also comprises the steps among the claim 1-112

During the very first time with antimicrobial and described ligand united using.

120. the method for claim 119 is not wherein used described antimicrobial in second time durations.

121. each method also comprises the steps among the claim 1-112

During the very first time with antifungal and described ligand united using.

122. the method for claim 121 is not wherein used described antimicrobial in second time durations.

123. each method also comprises the steps: among the claim 1-112

During the very first time with antitumor agent and described ligand united using.

124. the method for claim 123 is not wherein used described antitumor agent in second time durations.

125. each method among the claim 1-112, also be included in during the very first time in anticarcinogen and the described ligand united step of using.

126. the method for claim 125 is not wherein used described anticarcinogen in second time durations.

127. the method for claim 125 or claim 126; wherein said anticarcinogen is selected from down group: amycin; busulfan; carboplatin; chlorambucil; cisplatin; cyclophosphamide; ifosfamide; chlormethine; melphalan; procarbazine; the temozolomide; daunorubicin; doxorubicin; idarubicin; bleomycin; mitomycin; mitoxantrone; plicamycin; cytosine arabinoside; fluorouracil; hydroxyurea; methotrexate; asparaginase; pegaspargase; irinotecan; hycamtin; bicalutamide; estramustine; flutamide; leuprorelin; megestrol; nilutamide; testosterone; triptorelin; Anastrozole; letrozole; aldesleukin; alemtuzumab; gemtuzumab; toremifene; trastuzumab; etoposide; Docetaxel; paclitaxel; vinblastine; vincristine; vinorelbine; altretamine; erlotinib; gleevec; Rhizoma Curcumae Longae; tamoxifen; bortezomib; gefitinib; imatinib; be derived from 3; 4-methylene-dioxy-5,4 '-dimethoxy-3 '-the growth of cancer cells inhibitor of amino-Z-stilbene; his fourth and dibastic sodium phosphate prodrug thereof of oxybenzene; histone deacetylase inhibitors; octanedioyl aniline hydroxamic acid; Trichostatin A; sodium butyrate; metformin; five-lipoxidase (5-LO) antagonist; the antisense oligonucleotide of the RI α regulator subunit of targeting I type protein kinase A; vitamin E and analog thereof; tocopherol acid succinate (VES) and gene therapy.

128. each method among the claim 1-127, wherein

Described neurotransmitter system is the SP system;

Described acceptor type is the SP receptor;

Described part is the SP receptor stimulating agent; And

Described counter adaptation has caused the downward modulation of SP system.

129. the method for claim 128, wherein said counter adaptation are at least a in the following situation:

SP, NKA and/or NKB are terminal or by the biosynthesis of pituitary gland or discharge and reduce at receptor;

The decreased number of the binding site on receptor number and/or the receptor; With

Receptor pair reduces with the bonded sensitivity of SP receptor stimulating agent and/or SP, NKA and/or NKB.

130. each method among the claim 128-129, wherein said SP receptor stimulating agent are based on peptide.

131. each method among the claim 128-129, wherein said SP receptor stimulating agent are the analog of SP, NKA and/or NKB, or their pharmaceutically useful salt or derivant.

132. each method among the claim 128-129, wherein said SP receptor stimulating agent is the P material; The P material of free acid form; Biotin-P material; [Cys _3,6, Tyr ₈, Pro ₉]-P material; (disulphide bridges: 3-6), [Cys _3,6, Tyr ₈, Pro ₁₀]-P material; (disulphide bridges: 3-6), [4-chloro-Phe _7,8]-P material; [4-benzoyl-Phe ₈]-P material; [succinyl group-Asp ₆, N-Me-Phe ₈]-P material (6-11) (Senktide); [Tyr ₈]-P material; [Tyr ₉]-P material; Or shark P material peptide.

133. each method among the claim 128-129, wherein said SP receptor stimulating agent are NKA or the NKB analog with C-terminal seven peptides similar to NKA (4-10) or NKB (4-10), or its pharmaceutically useful salt or carrier.

134. each method among the claim 128-129, wherein said SP receptor stimulating agent is [Gln ⁴]-NKA, [GlN ⁴]-NKA (4-10), [Phe ⁷]-NKA, [Phe ⁷]-NKA (4-10), [Ile ⁷]-NKA, [Ile ⁷]-NKA (4-10), [Lys ⁵, MeLeu ⁹, Nle ¹⁰]-NKA (4-10), [Nle ¹⁰]-NKA (4-10), [β-Ala ⁸]-NKA (4-10), [Ala ⁵]-NKA (4-10), [Gln ⁴]-NKB, [GlN ⁴]-NKB (4-10), [Phe ⁷]-NKB, [Phe ⁷]-NKB (4-10), [Ile ⁷]-NKB, [Ile ⁷]-NKB (4-10), [Lys ⁵, MeLeu ⁹, Nle ¹⁰]-NKB (4-10), [Nle ¹⁰]-NKB (4-10), [β-Ala ⁸]-NKB (4-10), [Ala ⁵]-NKB (4-10), GR 73,632[δ-amino valeryl [Pro9, N-Me-Leu10]-P material (7-11)], [Glu (OBzl) 11] P material and hemokinin 1 (HK-1) (homologue of P material) or their pharmaceutically useful salt or carrier.

135. each method among the claim 128-129, wherein said SP receptor stimulating agent are [Arg]-NKB or its pharmaceutically useful salt or carrier.

136. each method among the claim 128-129, wherein said SP receptor stimulating agent is Val ⁷By alternate NKA of MePhe or NKB analog, or its pharmaceutically useful salt or carrier.

137. each method among the claim 128-136, wherein the predose of SP receptor stimulating agent is that about 0.1 to 100 μ g/kg/ days predose and 100 to 1000 μ g/kg/ days 8 hours slowly discharge.

138. each method among the claim 128-136, wherein the predose of SP receptor stimulating agent is that about 1 to 50 μ g/kg/ days predose and 20 to 50 μ g/kg/ days 8 hours slowly discharge.

139. each method among the claim 128-138, wherein said method are used for the treatment of bad spirit, nerve or physiological disorder among the patient.

140. the method for claim 139, wherein said bad spirit, nerve or physiological disorder are chronic pain, mood disorders, eating disorders, anxiety neurosis, motivation problem, psychoactive substance abuse, inflammatory disease, n or V, urinary incontinence, erythra, erythema or eruption.

141. the method for claim 139, wherein said bad spirit, nerve or physiological disorder are fibromyalgia, chronic fatigue syndrome, chronic back pain, chronic headache, chronic cancer pain, herpes zoster, reflex sympathetic dystrophy, neuropathy or inflammatory pain.

142. the method for claim 139, wherein said bad spirit, nerve or physiological disorder are the pain that expection occurs in the future.

Pain that 143. the method for claim 141, the pain that wherein said expection occurs in the future are medical procedures to be caused or because the pain that physical exertion causes.

144. the method for claim 139, wherein said bad spirit, nerve or physiological disorder are the sexual dysfunctions of major depression sexual disorders, wound retarded depression disease, temporary depressive emotion, manic depression, dysthymic disorder, popularity mood disorders, anhedonia or non-organic.

145. the method for claim 139, wherein said bad spirit, nerve or physiological disorder are gluttony, obesity, apositia or polyphagia.

146. the method for claim 139, wherein said bad spirit, nerve or physiological disorder are generalized anxiety disorder state, panic disorder, phobia, obsession, attention deficit companion hyperkinetic syndrome, Tourette's syndrome, hysteric sleep disease or breathe relevant sleep disease.

147. the method for claim 139, wherein said bad spirit, nerve or physiological disorder are because study or memory problems and amotivational.

148. the method for claim 139, wherein said bad spirit, nerve or physiological disorder are psychoactive substance abuses, and described material is selected from down group: anesthetis, ethanol, nicotine, analeptic, antianxiety drug, CNS inhibitor, psychedelic drug and Fructus Cannabis.

149. the method for claim 139, wherein said bad spirit, nerve or physiological disorder are the inflammation or the acute pancreatitis of asthma, arthritis, rhinitis, conjunctivitis, inflammatory bowel, skin or mucosa.

150. the method for claim 139, wherein said bad spirit, nerve or physiological disorder are the n or Vs that chemotherapy causes.

151. the method for claim 128-150, wherein said method is as the auxiliary treatment of cancer.

152. each method among the claim 128-151, wherein with use the relevant very first time at every turn during in do not use the SP receptor antagonist.

153. each method among the claim 128-152, wherein the SP receptor antagonist is used in one or more second time durations.

154. the method for claim 153, wherein the SP receptor antagonist is SR 48968, L-760735, CP-96,345, NKP608, L-AT, MK-869, L-742,694, L-733060, CP-99,994, P-122,721, CP 122,171, GSK 597599, GSK 679769, GSK 823296, saredutant, talnetant, Osanetant, and their pharmaceutically useful salt, analog and derivant.

155. the method for claim 154, wherein the predose of SP receptor antagonist is equal to 12mg/kg/ hour, continues 8 hours L-760735; About 30 μ g/kg/ hours CP-96,345; 0.1-10mg/kg/ the SSR240600 that uses; 0.01-0.1mg/kg/ the NKP608 that uses; The L-AT that 1-10mg/kg/ uses; 0.01-3mg/kg/ the MK-869 that uses; The L-742 of 1-30mg/kg, 694; The L-733 that 1-10mg/kg/ uses, 060; The CP-99 that 3-30mg/kg/ uses, 994 or CP-122,721; And the saredutant used of about 100mg/.

156. each method among the claim 128-155, wherein the downward modulation of SP system has produced the treatment benefit to bad spirit, nerve or physiological disorder.

157. each method among the claim 1-127, wherein

Described neurotransmitter system is an endogenous endorphins system;

Described acceptor type is μ and/or delta opiate receptor;

Described part is μ and/or delta opiate receptor antagonist; With

Described counter adaptation causes the rise of endogenous endorphins system.

158. the method for claim 157, wherein said counter adaptation are at least a in the following situation:

Endorphins is terminal and/or by the biosynthesis of pituitary gland or discharge and increase at receptor;

The number of the endorphins binding site on receptor number and/or the receptor increases; With

Receptor pair and μ and/or δ opiate agonist and/or the bonded sensitivity of endorphins increase.

159. each method among the claim 157-158, wherein said counter adaptation are at least a in the following situation:

Endorphins is terminal or by the biosynthesis of pituitary gland or discharge and increase at receptor;

The number of the endorphins binding site on receptor number and/or the receptor increases.

160. each method among the claim 157-159, wherein said μ and/or delta opiate receptor antagonist are specificity μ receptor antagonist or specificity δ receptor antagonist.

161. each method among the claim 157-159, wherein μ and/or delta opiate receptor antagonist are the specificity mu opioid receptor antagonists, it is selected from down group: clocinnamox mesylate, CTAP, CTOP, isothiocyanic acid etonitazene, β-funaltrexamine hydrochloride, two hydrochloric acid naloxonazines, Cyprodime, and their pharmaceutically useful salt, analog and derivant.

162. each method among the claim 157-159, wherein said μ and/or delta opiate receptor antagonist are the specificity delta opiate receptor antagonists, it is selected from down group: naltrindol, N-benzyl naltrindol HCl, maleic acid BNTX, ICI-154,129, ICI-174,864, naltriben mesylate, SDM25N HCl, 7-benzylidene naltrexone, and their pharmaceutically useful salt, analog and derivant.

163. each method among the claim 157-159, wherein said μ and/or delta opiate receptor antagonist are non-specific opiate antagonists.

164. each method among the claim 157-159, wherein said μ and/or delta opiate receptor antagonist are naloxone, naltrexone, nalmefene or nalbuphine, or their pharmaceutically useful salt, analog or derivant.

165. each method among the claim 157-159, wherein said delta opiate receptor antagonist are chemical compound or its N-oxide or its pharmaceutically useful salt with following structure

Wherein

R is pi-allyl, methacrylic, cyclopropyl methyl, dimethyl-allyl, tetrahydrofurfuryl or cyclobutylmethyl;

R ¹Be H, (C ₁-C ₁₈Alkyl)-, (C ₁-C ₁₈Alkyl)-CO-, (C ₁-C ₁₈Alkyl) ₂N-CO-, (C ₁-C ₁₈Alkyl)-SO ₂-, (C ₁-C ₁₈Alkyl)-O-CO-, Ph-CO-, Ph-SO ₂-, Ph-NH-CO, wherein each Ph one or more substituent groups of randomly being independently selected from down group replace: (C ₁-C ₁₂Alkyl), (C ₁-C ₁₂Alkyl)-O-, Cl, F, Br, I, CF ₃, R ⁴O-and R ⁴ ₂N-, wherein each R ⁴Be independently selected from down group: H, (C ₁-C ₄Alkyl), H-CO-and (C ₁-C ₄Alkyl)-CO-;

R ^2aAnd R ^2bBe selected from down independently of one another group: H, (C ₁-C ₆Alkyl), (C ₁-C ₆Alkyl)-O-, (C ₁-C ₆Alkyl)-CO-O-, R ⁵-O-, R ⁵ ₂N-, R ⁵-CO-NH-, R ⁵-S-and NO ₂, each R wherein ⁵Be independently selected from down group: H, (C ₁-C ₆Alkyl), (C ₃-C ₁₀Cycloalkyl), (C ₆-C ₁₀Aryl), (C ₁-C ₆Alkyl)-CO-, (C ₃-C ₁₀Cycloalkyl)-CO-, (C ₆-C ₁₀Aryl)-and CO-, wherein each randomly is selected from down 1-3 substituent group replacement of group: (C ₁-C ₁₂Alkyl), (C ₁-C ₁₂Alkyl)-O-, Cl, F, Br, I, CF ₃, R ⁴O-and R ⁴ ₂N-; Perhaps R ^2aAnd R ^2bForm O=or CH together ₂=; With

R ³Be H, OH, CH ₃Or OCH ₃

166. the method for claim 165, wherein R is a pi-allyl.

167. the method for claim 165 or claim 166, wherein R ¹Not H.

168. the method for claim 165 or claim 166, wherein R ¹It is neighbour-amino benzoyl or neighbour-(acetoxyl group) benzoyl.

169. the method for claim 165 or claim 166, wherein R ¹Be (C ₁-C ₁₈Alkyl) or (C ₁-C ₁₈Alkyl) CO-.

170. the method for claim 165 or claim 166, wherein R ¹Be (C ₁-C ₆Alkyl) CO-.

171. each method, wherein R among the claim 165-170 ^2aAnd R ^2bDo not form O=together.

172. each method, wherein R among the claim 165-170 ^2aAnd R ^2bBe H, or form CH together ₂=.

173. each method, wherein R among the claim 165-172 ³Not OH.

174. each method among the claim 161-173, wherein the predose of μ and/or delta opiate receptor antagonist is equal to about 2mg/ and is applied to the naloxone that about 200mg/ uses.

175. each method among the claim 161-173, wherein the predose of μ and/or delta opiate receptor antagonist is equal to about 10mg/ and is applied to the naloxone that about 100mg/ uses.

176. each method among the claim 157-158, wherein said μ and/or delta opiate receptor antagonist are naloxone or its pharmaceutically useful salt or prodrug.

177. the method for claim 176, wherein each dosage of naloxone is higher than 10mg/ and uses; Being higher than 10.5mg/ uses; Being higher than 11mg/ uses; Or be higher than 15mg/ and use.

178. each method among the claim 176-177, wherein the predose of naloxone is that 10-50mg/ uses.

179. each method among the claim 176-177, wherein the predose of naloxone is that 5-500mg/ uses.

180. each method among the claim 176-179, wherein the maximal dose of naloxone is not higher than 3000mg/ and uses.

181. each method among the claim 157-180 wherein uses time-delay-release or slow releasing preparation to use μ and/or delta opiate receptor antagonist.

182. each method among the claim 157-180, in wherein said μ and/or delta opiate receptor antagonist oral administration, transdermal, the spinal cord, in the sheath, by suck, subcutaneous, intravenous, intramuscular, saturating mucosa or use via osmotic pumps, microcapsule, implant or suspension.

183. each method among the claim 157-180, wherein transdermal administration μ and/or delta opiate receptor antagonist.

184. each method among the claim 181-183, wherein μ and/or delta opiate receptor antagonist are 2-12 hour in the persistent period; Persistent period is 2-6 hour or persistent period to be to discharge in 6-12 hour the time durations.

185. each method among the claim 157-180, wherein μ and/or delta opiate receptor antagonist are used as the loading dose of fast Absorption.

186. each method among the claim 157-180, wherein μ and/or delta opiate receptor antagonist use the loading dose of fast Absorption and transdermal administration or or slowly with time-delay-delivery formulations-form of the preparation of release uses.

187. each method among the claim 157-186, wherein specificity μ and/or δ receptor antagonist and non-specific μ and/or δ receptor antagonist are used substantially simultaneously.

188. each method among the claim 157-186, wherein specificity μ and/or δ receptor antagonist and non-specific μ and/or δ receptor antagonist are used in proper order.

189. each method among the claim 157-188, wherein said bad spirit, nerve or physiological disorder are the wounds of pain, mood disorders, eating disorders, anxiety neurosis, motivation problem, psychoactive substance abuse, motivation or performance deficiency, immune system relevant disease and needs healing.

190. each method among the claim 157-189, wherein said method are used for the treatment of bad spirit, nerve or physiological disorder among the patient.

191. the method for claim 190, wherein said bad spirit, nerve or physiological disorder are pain, chronic pain syndrome or acute pain that expection occurs in the future.

192. the pain that the method for claim 190, wherein said bad spirit, nerve or physiological disorder are expections to be occurred owing to operation in the future, expection are because pain, fibromyalgia, chronic fatigue syndrome, chronic back pain, chronic headache, herpes zoster, reflex sympathetic dystrophy, neuropathy, inflammatory pain or the chronic cancer pain that the physical exertion in future occurs.

193. the method for claim 190, wherein said bad spirit, nerve or physiological disorder are the sexual dysfunctions of major depression sexual disorders, wound retarded depression disease, temporary depressive emotion, manic depression, dysthymic disorder, popularity mood disorders, anhedonia or non-organic.

194. the method for claim 190, wherein said bad spirit, nerve or physiological disorder are gluttony, obesity, apositia or polyphagia.

195. the method for claim 190, wherein said bad spirit, nerve or physiological disorder are generalized anxiety disorder state, panic disorder, Tourette's syndrome, hysteric sleep disease or breathe relevant sleep disease.

196. the method for claim 190, wherein said bad spirit, nerve or physiological disorder are because the motivation that study or memory problems cause lacks.

197. the method for claim 190, wherein said bad spirit, nerve or physiological disorder are psychoactive substance abuses, and described material is selected from down one or more of group: anesthetis, ethanol, nicotine, analeptic, antianxiety drug, CNS inhibitor, psychedelic drug and Fructus Cannabis.

198. the method for claim 190, wherein said bad spirit, nerve or physiological disorder are the motivations of required spirit or physical exertion or prepare not enough.

199. 198 methods of claim, wherein required activity is physical training, sports, study or test.

200. each method among the claim 157-199, wherein said method is as the auxiliary treatment of cancer, infection, AIDS or wound.

Each method among the claim 157-200, wherein with use the relevant very first time at every turn during in do not use μ and/or delta opiate receptor agonist.

Each method among the claim 157-201, wherein μ and/or delta opiate receptor agonist are used in one or more second time durations.

Each method among the claim 157-201, wherein the CRF receptor antagonist is used in one or more second time durations.

The method of claim 203, wherein said CRF receptor antagonist is selected from down group: R121919, DMP696, antalarmin, CP-154,526, SSR125543A, 2-arylamino-4-trifluoromethyl-amino methyl thiazole antagonist, astressin, alpha-helix CRF chemical compound, and their pharmaceutically useful salt, analog and derivant.

Each method among the claim 157-204, wherein that CRF receptor stimulating agent and μ and/or delta opiate receptor antagonist is repeatedly co-administered, at every turn using of CRF receptor stimulating agent has the half life of using, wherein use half life and use between during ratio be not more than 1/2.

Each method among the claim 157-204, wherein the CRF receptor stimulating agent is used in one or more second time durations.

Each method among the claim 157-206, wherein the rise of endogenous endorphins system has produced the treatment benefit to bad spirit, nerve or the physiological disorder relevant with μ and/or delta opiate receptor.

Each method among the claim 1-127, wherein

Described neurotransmitter system is the dynorphin system;

The type of described receptor is a kappa receptor;

Described part is the kappa receptor agonist; With

Described counter adaptation causes the downward modulation of dynorphin system.

The method of claim 208, wherein counter adaptation is at least a in the following situation:

Dynorphin is terminal or by the biosynthesis of pituitary gland or discharge and reduce at receptor;

The decreased number of the binding site on kappa receptor number and/or the kappa receptor; With

Kappa receptor pair reduces with kappa receptor agonist and/or the bonded sensitivity of dynorphin.

210. each method among the claim 208-209, wherein the kappa receptor agonist is based on peptide.

211. each method among the claim 208-209, wherein the kappa receptor agonist is dynorphin or its pharmaceutically useful salt, carrier or analog.

212. each method among the claim 208-209, wherein the kappa receptor agonist is non-benzmorphan; Enadoline; PD117302; CAM569; PD123497; GR89,696; U69,593; TRK-820; Trans-3,4-two chloro-N-methyl-N-[1-(1-pyrrolidinyl) cyclohexyl] benzene-acetamide; Asimadoline (EMD-61753); Phenyl acetamide; Tetrahydro-1,4-thiazine; Piperidines; Benzo [b] thiophene-4-acetamide; Trans-(+/-)-(PD-117302); 4-benzofuran acetamide (PD-129190); 2,6-methylene-3-benzene Zha Zuoxin-8-alcohol (MR-1268); Morphinan-3-alcohol (KT-90); GR-45809; 1-piperazine carboxylic acid (GR-89696); GR-103545; Piperazine; GR-94839; Xorphanol; Phenyl acetamide (RU-49679); Fedotozine; Phenyl acetamide (DuP-747); HN-11608; Apadoline (RP-60180); The spiradoline mesylate; Phenyl acetamide is trans-the U-50488 metilsulfate; 3FLB; FE200665; FE200666; The analog of MPCB-GRRI or MPCB-RRI, the segmental analog of C-terminal of dynorphin A (1-8), or their pharmaceutically useful salt or carrier.

213. each method among the claim 208-212, wherein the predose of kappa receptor agonist is equal to the dynorphin that 0.0005-0.05mg/kg/ uses; The enadoline that 5-700mg/ uses; The FE20665 that 1-500 μ g/ uses; The U69 that 0.5-100 μ g/ uses, 0.01-1mg/kg/ uses, 593; 0.05-5mg/kg/ the TRK820 that uses; 0.01-1mg/kg/ the U 50 488 that uses; Or the PD 117302 that uses of 0.01-1mg/kg/.

214. each method among the claim 208-212, wherein the predose of kappa receptor agonist is equal to the dynorphin that 0.005-0.02mg/kg/ uses; The enadoline that 100-500mg/ uses; The FE 20665 that 3-100 μ g/ uses; The FE 20666 that 1-80 μ g/ uses; 0.1-0.7mg/kg/ the U69 that uses, 593; 0.5-3mg/kg/ the TRK 820 that uses; 0.5-7mg/kg/ the PD 117302 that U 50 488 that uses or 0.1-0.7mg/kg/ use.

215. each method among the claim 208-212, wherein the kappa receptor agonist is Salvinorin A or its analog or prodrug.

216. the method for claim 215, wherein the predose of Salvinorin A is that 5-200 μ g/ uses.

217. each method among the claim 215-216, wherein the maximal dose of Salvinorum A is that at least 5000 μ g/ use.

218. each method among the claim 215-217, the wherein saturating mucosal administration of Salvinorin A.

219. each method among the claim 215-218, wherein Salvinorum A uses as slow-delivery formulations.

220. the method for claim 219, wherein Salvinorum A the persistent period be 2-6 hour during use.

221. each method among the claim 208-220 is wherein used basically simultaneously based on the kappa receptor agonist of peptide and non-kappa receptor agonist based on peptide.

222. each method among the claim 208-220 is wherein used in proper order based on the kappa receptor agonist of peptide and non-kappa receptor agonist based on peptide.

223. each method among the claim 208-222, wherein said method are used for the treatment of bad spirit, nerve or physiological disorder among the patient.

224. the method for claim 223, wherein said disease are that pain, mood disorders, eating disorders, anxiety disorder, motivation problem, psychoactive substance abuse or motivation or performance are not enough.

225. the method for claim 223, wherein said disease are the pain that expection occurs in the future; Chronic pain syndrome; Or acute pain.

226. the pain that the method for claim 223, wherein said disease are expections to be occurred owing to operation in the future, expection are because pain, fibromyalgia, chronic fatigue syndrome, chronic back pain, chronic headache, herpes zoster, reflex sympathetic dystrophy, neuropathy, inflammatory pain or the chronic cancer pain that the physical exertion in future occurs.

227. the method for claim 223, wherein said disease are major depression sexual disorders; Wound retarded depression disease; Temporary depressive emotion; Manic depression; Dysthymic disorder; The popularity mood disorders; The sexual dysfunction of anhedonia or non-organic.

228. the method for claim 223, wherein said disease is gluttony; Obesity; Apositia or polyphagia.

229. the method for claim 223, wherein said disease are the generalized anxiety disorder states; Panic disorder; Tourette's syndrome; Hysteric sleep disease; Or the relevant sleep disease of breathing.

230. the method for claim 223, wherein said disease are because the motivation that study or memory problems cause lacks.

231. the method for claim 223, wherein said disease is psychoactive substance abuse, and described material is selected from down one or more of group: anesthetis, ethanol, nicotine, analeptic, antianxiety drug, CNS inhibitor, psychedelic drug and Fructus Cannabis.

232. the method for claim 223, wherein said disease are the motivations of required spirit or physical exertion or prepare not enough.

233. the method for claim 232, wherein required activity is a fitness training; Sports; Study or test.

234. each method among the claim 208-233, wherein said method is as the auxiliary treatment of cancer.

235. each method among the claim 208-234, wherein with use the relevant very first time at every turn during in do not use the kappa receptor antagonist.

236. each method among the claim 208-234, wherein the kappa receptor antagonist is used in one or more second time durations.

237. each method among the claim 208-236, wherein the downward modulation of dynorphin system has produced the treatment benefit to bad spirit, nerve or the physiological disorder relevant with kappa receptor.

238. each method among the claim 1-127, wherein

Described neurotransmitter system is the 5-hydroxy tryptamine system; And

Described counter adaptation has caused the rise of 5-hydroxy tryptamine system.

239. the method for claim 238, wherein

Described acceptor type is the 5-hydroxy tryptamine presynaptic autoreceptor; With

Described part is a 5-hydroxy tryptamine presynaptic autoreceptor agonist.

240. the method for claim 239, wherein said counter adaptation are at least a in the following situation:

5-hydroxy tryptamine increases in the biosynthesis and/or the release of synaptic space;

The absorption again of 5-hydroxy tryptamine reduces;

5-hydroxy tryptamine presynaptic autoreceptor decreased number;

The 5-hydroxy tryptamine presynaptic autoreceptor reduces the sensitivity of 5-hydroxy tryptamine and/or 5-hydroxy tryptamine presynaptic autoreceptor agonist;

5-hydroxy tryptamine postsynaptic receptor number increases; Or

The 5-hydroxy tryptamine postsynaptic receptor increases the sensitivity of 5-hydroxy tryptamine or 5-hydroxy tryptamine postsynaptic receptor agonist.

241. each method among the claim 239-240, wherein the 5-hydroxy tryptamine presynaptic autoreceptor is 5HT _1AAutoreceptor and/or 5HT _1BAutoreceptor.

242. each method among the claim 239-242, wherein 5-hydroxy tryptamine presynaptic autoreceptor agonist is EMD-68843, buspirone, gepirone, ipsapirone, tandospirone, lesopitron, zalospirone, MDL-73005EF or BP-554.

243. each method among the claim 239-242, wherein the predose of 5-hydroxy tryptamine presynaptic autoreceptor agonist is equal to EMD-68843, the buspirone that 1-500mg/ uses, the lesopitron that 1-500mg/ uses, the gepirone that 1-500mg/ uses, the tandospirone of 5-500mg or the zalospirone of 1-200mg that 1-400mg/ uses.

244. each method among the claim 239-242, wherein the predose of 5-hydroxy tryptamine presynaptic autoreceptor agonist is equal to EMD-68843, the buspirone that 10-100mg/ uses, the lesopitron that 10-200mg/ uses, the gepirone that 10-100mg/ uses, the tandospirone of 20-200mg or the zalospirone of 10-100mg that 10-100mg/ uses.

245. each method among the claim 239-244, wherein with use the relevant very first time at every turn during in do not use 5-hydroxy tryptamine presynaptic autoreceptor antagonist.

246. each method among the claim 239-245, wherein 5-hydroxy tryptamine presynaptic autoreceptor antagonist is used in one or more second time durations.

247. the method for claim 238, wherein

Described acceptor type is the 5-hydroxy tryptamine postsynaptic receptor; With

Described part is a 5-hydroxy tryptamine postsynaptic autoreceptor antagonist.

248. the method for claim 247, wherein said counter adaptation are at least a in the following situation:

The absorption again of 5-hydroxy tryptamine reduces;

The number of 5-hydroxy tryptamine postsynaptic receptor increases;

The 5-hydroxy tryptamine postsynaptic receptor increases the sensitivity of 5-hydroxy tryptamine and/or 5-hydroxy tryptamine postsynaptic receptor agonist;

The decreased number of 5-hydroxy tryptamine presynaptic autoreceptor;

The 5-hydroxy tryptamine presynaptic autoreceptor reduces the sensitivity of 5-hydroxy tryptamine and/or 5-hydroxy tryptamine presynaptic autoreceptor agonist.

249. each method among the claim 247-248, wherein the 5-hydroxy tryptamine postsynaptic receptor is 5HT ₁Receptor; 5HT ₂Receptor; 5HT ₃Receptor; 5HT ₄Receptor; 5HT ₅Receptor; 5HT ₆Receptor; 5HT ₇Receptor; Or the receptor of its hypotype.

250. each method among the claim 247-249, wherein 5-hydroxy tryptamine postsynaptic receptor antagonist is (S)-WAY-100135, WAY-100635, buspirone, gepirone, ipsapirone, tandospirone, lesopitron, zalospirone, MDL-73005EF or BP-554.

251. each method among the claim 247-250, wherein the predose of 5-hydroxy tryptamine postsynaptic receptor antagonist is equal to the WAY-100635 that about 0.01-5mg/kg/ uses.

252. each method among the claim 247-250, wherein the predose of 5-hydroxy tryptamine postsynaptic receptor antagonist is equal to the WAY-100635 that about 0.025-1mg/kg/ uses.

253. each method is further comprising the steps of among the claim 247-252

5-hydroxy tryptamine presynaptic autoreceptor agonist and 5-hydroxy tryptamine postsynaptic receptor antagonist combination are used.

254. each method among the claim 247-252, wherein 5-hydroxy tryptamine postsynaptic receptor antagonist also is a 5-hydroxy tryptamine presynaptic autoreceptor agonist.

255. each method among the claim 247-254, wherein with use the relevant very first time at every turn during in do not use 5-hydroxy tryptamine postsynaptic receptor agonist.

256. each method among the claim 247-255, wherein 5-hydroxy tryptamine postsynaptic receptor agonist is used in one or more second time durations.

257. each method is further comprising the steps of among the claim 238-256

With norepinephrine presynaptic alpha-2 adrenergic receptor agonists and/or norepinephrine postsynaptic adrenergic aceptor antagonist and ligand united using.

258. each method among the claim 238-257 has wherein produced the treatment benefit to raising 5-hydroxy tryptamine system and receptor related bad spirit, nerve or physiological disorder.

259. each method among the claim 1-127, wherein

Described neurotransmitter system is the norepinephrine system; And

Described counter adaptation causes the rise of norepinephrine system.

260. the method for claim 259, wherein

Described acceptor type is a norepinephrine presynaptic alpha-2 adrenergic receptor;

Described part is a norepinephrine presynaptic alpha-2 adrenergic receptor agonists.

261. the method for claim 260, wherein said counter adaptation are at least a in the following situation:

Norepinephrine increases in the biosynthesis and/or the release of synaptic space;

The absorption again of norepinephrine reduces;

The decreased number of norepinephrine presynaptic alpha-2 adrenergic receptor;

Norepinephrine presynaptic alpha-2 adrenergic receptor reduces the sensitivity of norepinephrine and/or norepinephrine presynaptic alpha-2 adrenergic receptor agonists;

The number of norepinephrine postsynaptic adrenoreceptor increases; Or

Norepinephrine postsynaptic adrenoreceptor increases the sensitivity of norepinephrine and/or norepinephrine postsynaptic 3 adrenergic receptor agonists.

262. each method among the claim 260-261, wherein norepinephrine presynaptic alpha-2 adrenergic receptor agonists is clonidine, guanfacine, lofexidine, detomidine, dexmedetomidine, mivazerol or Alpha-Methyl norepinephrine.

263. each method among the claim 260-262, wherein the predose of norepinephrine presynaptic alpha-2 adrenergic receptor agonists is equal to the Alpha-Methyl norepinephrine that clonidine that 0.1-10 μ g/kg/ uses, guanfacine that 0.01-10mg/ uses, lofexidine that 0.01-1mg/ uses, detomidine that 1-100 μ g/kg/ uses, dexmedetomidine that 0.05-5 μ g/kg/ uses, mivazerol that 0.05-10 μ g/kg/ uses or 5-500ng/kg/ use.

264. each method among the claim 260-262, wherein the predose of norepinephrine presynaptic alpha-2 adrenergic receptor agonists is equal to the Alpha-Methyl norepinephrine that clonidine that 0.1-0.5mg/ uses, guanfacine that 0.1-5mg/ uses, lofexidine that 0.05-0.5mg/ uses, detomidine that 10-80 μ g/kg/ uses, dexmedetomidine that 0.1-3 μ g/kg/ uses, mivazerol that 0.5-5 μ g/kg/ uses or 10-100ng/kg/ use.

265. each method among the claim 260-262, wherein with use the relevant very first time at every turn during in do not use norepinephrine presynaptic alpha-2 adrenergic receptor antagonist.

266. each method among the claim 260-263, wherein norepinephrine presynaptic alpha-2 adrenergic receptor antagonist is used in one or more second time durations.

267. the method for claim 259, wherein

Described acceptor type is a norepinephrine postsynaptic adrenoreceptor;

Described part is a norepinephrine postsynaptic adrenergic aceptor antagonist; And

Described bad spirit, nerve or physiological disorder and norepinephrine postsynaptic adrenoreceptor negative correlation.

268. the method for claim 267, wherein said counter adaptation are at least a in the following situation:

The absorption again of norepinephrine reduces;

The number of norepinephrine postsynaptic adrenoreceptor increases;

Norepinephrine postsynaptic adrenoreceptor increases the sensitivity of norepinephrine and/or norepinephrine postsynaptic 3 adrenergic receptor agonists;

The decreased number of norepinephrine presynaptic alpha-2 adrenergic receptor; Or

Norepinephrine presynaptic alpha-2 adrenergic receptor reduces the sensitivity of norepinephrine and/or norepinephrine presynaptic alpha-2 adrenergic receptor agonists.

269. each method among the claim 267-268, wherein norepinephrine postsynaptic adrenoreceptor is the α receptor; Beta receptor; Or the receptor of its hypotype.

270. each method among the claim 267-269, wherein norepinephrine postsynaptic adrenergic aceptor antagonist is idazoxan, SKF 104078 or SKF 104856.

271. each method among the claim 267-270, wherein the predose of norepinephrine postsynaptic adrenergic aceptor antagonist is equal to the idazoxan that 0.5-100mg/ uses.

272. each method among the claim 267-270, wherein the predose of norepinephrine postsynaptic adrenergic aceptor antagonist is equal to the idazoxan that 5-50mg/ uses.

273. each method is further comprising the steps of among the claim 267-272

Norepinephrine presynaptic alpha-2 adrenergic receptor agonists and norepinephrine postsynaptic adrenergic aceptor antagonist is co-administered.

274. each method among the claim 267-272, wherein norepinephrine postsynaptic adrenergic aceptor antagonist also is a norepinephrine presynaptic alpha-2 adrenergic receptor agonists.

275. each method among the claim 267-274, wherein with use the relevant very first time at every turn during in do not use norepinephrine postsynaptic 3 adrenergic receptor agonists.

276. each method among the claim 267-275, wherein norepinephrine postsynaptic 3 adrenergic receptor agonists is used in one or more second time durations.

277. each method is further comprising the steps of among the claim 267-276

With 5-hydroxy tryptamine presynaptic autoreceptor agonist or 5-hydroxy tryptamine postsynaptic receptor antagonist and described ligand united using.

278. each method among the claim 259-277, described method are used for the treatment of bad spirit, nerve or physiological disorder among the patient, described bad spirit, nerve or physiological disorder are relevant with 5-hydroxytryptamine receptor.

279. right is wanted 278 method, wherein said disease is mood disorders, eating disorders, pain obstacle, psychoactive substance abuse, anxiety disorder or obsession.

280. each method among the claim 259-278, wherein said method is as the auxiliary treatment of cancer.

281. each method among the claim 259-279, wherein the rise of norepinephrine system is to having produced the treatment benefit with receptor related bad spirit, nerve or physiological disorder.

282. each method among the claim 1-127, wherein

Described neurotransmitter system is a described CRF system;

Described acceptor type is the CRF receptor;

Described part is the CRF receptor stimulating agent; With

Described counter adaptation causes the downward modulation of CRF system.

283. the method for claim 282, wherein said counter adaptation are at least a in the following situation:

Corticotropin-releasing factor is by hypothalamic biosynthesis or discharge minimizing;

The decreased number of the binding site on the number of CRF receptor and/or the CRF receptor; With

Described receptor pair reduces with CRF receptor stimulating agent and/or the bonded sensitivity of corticotropin-releasing factor.

284. each method among the claim 282-283, wherein said CRF receptor stimulating agent are based on peptide.

285. each method among the claim 282-283, wherein said CRF receptor stimulating agent are the analog of corticotropin-releasing factor, or its pharmaceutically useful salt or derivant.

286. each method among the claim 282-283, wherein said CRF receptor stimulating agent is cortagine.

287. each method among the claim 282-286, the predose of wherein said CRF receptor stimulating agent be about 0.1 to 100 μ g/kg/ days predose and 100 to 1000 μ g/kg/ days, continue 8 hours slow release.

288. each method among the claim 282-286, the predose of wherein said CRF receptor stimulating agent be about 1 to 50 μ g/kg/ days predose and 20 to 50 μ g/kg/ days, continue 8 hours slow release.

289. each method among the claim 282-288, wherein said method are used for the treatment of bad spirit, nerve or physiological disorder among the patient, described bad spirit, nerve or physiological disorder and CRF receptor positive correlation.

290. the method for claim 289, wherein said bad spirit, nerve or physiological disorder are the inhibitable type depressions.

291. the method for claim 289, wherein said bad spirit, nerve or physiological disorder are the memory deficiencies.

292. the method for claim 289, wherein said bad spirit, nerve or physiological disorder are anxiety or the disease relevant with anxiety.

293. the method for claim 289, wherein said bad spirit, nerve or physiological disorder are the very few obstacles of feed.

The needs that the memory that 294. the method for claim 289, wherein said bad spirit, nerve or physiological disorder are expections to be taken place in the future increases.

295. the method for claim 289, wherein said bad spirit, nerve or physiological disorder be expected at take place in the future stress.

296. the method for claim 289, wherein said bad spirit, nerve or physiological disorder are stress disorders after the wound.

297. the method for claim 289, wherein said bad spirit, nerve or physiological disorder are inappetence.

298. the method for claim 289, wherein said bad spirit, nerve or physiological disorder are because the motivation that study or memory problems cause lacks.

In 299. each method among the claim 282-298, wherein said method also are included in during the very first time that μ and/or delta opiate receptor antagonist and CRF agonist is co-administered, its use half life and use between during ratio be not more than 1/2.

300. each method among the claim 282-299, wherein with use the relevant very first time at every turn during in neither use the CRF receptor antagonist and also do not use the AVP receptor antagonist.

Each method among the claim 282-300, wherein CRF receptor antagonist and/or AVP receptor antagonist one or more with use the second relevant time durations at every turn in use.

The method of claim 301, wherein said CRF receptor antagonist is selected from down one or more of group: R121919, DMP696, antalarmin, CP-154,526, SSR125543A, 2-arylamino-4-trifluoromethyl-amino methyl thiazole antagonist, astressin, alpha-helix CRF chemical compound, and their pharmaceutically useful salt, analog and derivant.

Each method among the claim 282-302, the downward modulation of wherein said CRF system is to having produced the treatment benefit with the positively related bad spirit of CRF receptor, nerve or physiological disorder.

Each method among the claim 1-127, wherein

Described neurotransmitter system is a described CRF system;

Described acceptor type is the CRF receptor;

Described part is the CRF receptor antagonist; With

Described counter adaptation causes the rise of CRF system.

The method of claim 304, wherein said counter adaptation are at least a in the following situation:

Corticotropin-releasing factor is by hypothalamic biosynthesis or discharge increase;

The number of the binding site on the number of CRF receptor and/or the CRF receptor increases; With

Described receptor pair increases with CRF receptor stimulating agent and/or the bonded sensitivity of corticotropin-releasing factor.

Each method among the claim 304-305, wherein said CRF receptor antagonist is selected from down one or more of group: R121919, DMP696, antalarmin, CP-154,526, SSR125543A, 2-arylamino-4-trifluoromethyl-amino methyl thiazole antagonist, astressin, alpha-helix CRF chemical compound, and their pharmaceutically useful salt, analog and derivant.

Each method among the claim 304-306, the predose of wherein said CRF receptor antagonist be about 0.1 to 100 μ g/kg/ days predose and 100 to 1000 μ g/kg/ days, continue 8 hours slow release.

Each method among the claim 304-306, the predose of wherein said CRF receptor antagonist be about 1 to 50 μ g/kg/ days predose and 20 to 50 μ g/kg/ days, continue 8 hours slow release.

Each method among the claim 304-308, wherein said method are used for the treatment of bad spirit, nerve or physiological disorder among the patient, described bad spirit, nerve or physiological disorder and CRF receptor negative correlation.

310. the method for claim 309, wherein said bad spirit, nerve or physiological disorder are atypical depressions.

311. the method for claim 309, wherein said bad spirit, nerve or physiological disorder are weight increase or disease of eating too much at one meal.

312. the method for claim 309, wherein said bad spirit, nerve or physiological disorder are drowsiness or tired.

In 313. each method among the claim 304-312, wherein said method also are included in during the very first time that μ and/or delta opiate receptor antagonist and CRF agonist is co-administered, its use half life and use between during ratio be not more than 1/2.

314. each method among the claim 304-313, wherein with use the relevant very first time at every turn during in neither use the CRF receptor stimulating agent and also do not use the AVP receptor stimulating agent.

315. each method among the claim 304-314, wherein CRF receptor stimulating agent and/or AVP receptor stimulating agent one or more with use the second relevant time durations at every turn in use.

316. the method for claim 315, wherein said CRF receptor stimulating agent are the analog of corticotropin-releasing factor, cortagine or their pharmaceutically useful salt or derivant.

317. each method among the claim 304-316, the downward modulation of wherein said CRF system has produced the treatment benefit to bad spirit, nerve or physiological disorder with CRF receptor negative correlation.

318. each method among the claim 1-127, wherein

Described neurotransmitter system is the AVP system;

Described acceptor type is the AVP receptor;

Described part is the AVP receptor stimulating agent; With

Described counter adaptation causes the downward modulation of AVP system.

319. the method for claim 318, wherein said counter adaptation are at least a in the following situation:

Arginine vasopressin is by hypothalamic biosynthesis or discharge minimizing;

The decreased number of the binding site on the number of AVP receptor and/or the AVP receptor; With

Described receptor pair reduces with AVP receptor stimulating agent and/or the bonded sensitivity of arginine vasopressin.

320. each method among the claim 318-319, wherein said AVP receptor stimulating agent are based on peptide.

321. each method among the claim 318-319, wherein said AVP receptor stimulating agent are selected from down group one or more: felypressin, Desmopressin and their pharmaceutically useful salt, analog and derivant.

322. each method among the claim 318-321, the predose of wherein said AVP receptor stimulating agent be about 0.1 to 100 μ g/kg/ days predose and 100 to 1000 μ g/kg/ days, continue 8 hours slow release.

323. each method among the claim 318-321, the predose of wherein said AVP receptor stimulating agent be about 1 to 50 μ g/kg/ days predose and 20 to 50 μ g/kg/ days, continue 8 hours slow release.

324. each method among the claim 318-323, wherein said method are used for the treatment of bad spirit, nerve or physiological disorder among the patient, described bad spirit, nerve or physiological disorder and AVP receptor positive correlation.

325. the method for claim 324, wherein said bad spirit, nerve or physiological disorder are the inhibitable type depressions.

326. the method for claim 324, wherein said bad spirit, nerve or physiological disorder are the memory deficiencies.

327. the method for claim 324, wherein said bad spirit, nerve or physiological disorder are anxiety or the disease relevant with anxiety.

328. the method for claim 324, wherein said bad spirit, nerve or physiological disorder are the very few obstacles of feed.

The needs that the memory that 329. the method for claim 324, wherein said bad spirit, nerve or physiological disorder are expections to be taken place in the future increases.

330. the method for claim 324, wherein said bad spirit, nerve or physiological disorder be expected at take place in the future stress.

331. the method for claim 324, wherein said bad spirit, nerve or physiological disorder are stress disorders after the wound.

332. the method for claim 324, wherein said bad spirit, nerve or physiological disorder are inappetence.

333. the method for claim 324, wherein said bad spirit, nerve or physiological disorder are because the motivation that study or memory problems cause lacks.

It is co-administered that 334. each method among the claim 318-333, wherein said method also comprise μ and/or delta opiate receptor antagonist and AVP receptor stimulating agent, its use half life and use between during ratio be not more than 1/2.

It is co-administered that 335. each method among the claim 318-334, wherein said method also comprise CRF receptor stimulating agent and AVP receptor stimulating agent, its use half life and use between during ratio be not more than 1/2.

336. each method among the claim 318-325, wherein with use the relevant very first time at every turn during in neither use the CRF receptor antagonist and also do not use the AVP receptor antagonist.

337. each method among the claim 318-336, wherein CRF receptor antagonist and/or AVP receptor antagonist one or more with use the second relevant time durations at every turn in use.

338. the method for claim 337, wherein said AVP receptor antagonist are selected from down group one or more: d (CH2) 5Tyr (Me) AVP, Phaa-d-Tyr (Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH ₂, [Lys (3N ₃Phpa) ⁸] HO-LVA, [d (CH2) 5, D-Ile2, Ile4]-AVP and [ ¹²⁵I]-d (CH2) 5[D-Tyr (Et) 2, Val4, Tyr-NH29] AVP, OPC-21268 (1-(1-[4-(3-acetyl-amino propoxyl group) benzoyl]-the 4-piperidyl)-3,4-dihydro-2 (1H)-quinolinone); R 49059; OPC-31260 (5-dimethylamino-1-[4-(2-methyl benzoyl amino) benzoyl]-2,3,4,5-tetrahydrochysene-1H-benzo-aza

); Conivaptan; VPA 985 and YM 471[(Z)-4 '-[4,4-two fluoro-5-[2-(4-dimethylamino piperidino)-2-oxo ethylidene]-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza

-1-carbonyl]-2-phenyl benzanilide mono-hydrochloric salts] and their pharmaceutically useful salt, analog and derivant.

339. each method among the claim 318-338, the downward modulation of wherein said described AVP system has produced the treatment benefit to bad spirit, nerve or the physiological disorder relevant with the AVP receptor.

340. each method among the claim 1-127, wherein

Described neurotransmitter system is a described AVP system;

Described acceptor type is the AVP receptor;

Described part is the AVP receptor antagonist; With

Described counter adaptation causes the rise of AVP system.

341. the method for claim 340, wherein said counter adaptation are at least a in the following situation:

Arginine vasopressin is by hypothalamic biosynthesis or discharge increase;

The number of the binding site on the number of AVP receptor and/or the AVP receptor increases; With

Described receptor pair increases with AVP receptor stimulating agent and/or the bonded sensitivity of arginine vasopressin.

342. each method among the claim 340-341, wherein said AVP receptor antagonist are selected from down group one or more: d (CH2) 5Tyr (Me) AVP, Phaa-d-Tyr (Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH ₂, [Lys (3N ₃Phpa) ⁸] HO-LVA, [d (CH2) 5, D-Ile2, Ile4]-AVP and [ ¹²⁵I]-d (CH2) 5[D-Tyr (Et) 2, Val4, Tyr-NH29] AVP, OPC-21268 (1-(1-[4-(3-acetyl-amino propoxyl group) benzoyl]-the 4-piperidyl)-3,4-dihydro-2 (1H)-quinolinone); R 49059; OPC-31260 (5-dimethylamino-1-[4-(2-methyl benzoyl amino) benzoyl]-2,3,4,5-tetrahydrochysene-1H-benzo-aza

343. each method among the claim 340-342, the predose of wherein said AVP receptor antagonist be about 0.1 to 100 μ g/kg/ days predose and 100 to 1000 μ g/kg/ days, continue 8 hours slow release.

344. each method among the claim 340-342, the predose of wherein said AVP receptor antagonist be about 1 to 50 μ g/kg/ days predose and 20 to 50 μ g/kg/ days, continue 8 hours slow release.

345. each method among the claim 340-344, wherein said method are used for the treatment of bad spirit, nerve or physiological disorder among the patient, described bad spirit, nerve or physiological disorder and AVP receptor negative correlation.

346. the method for claim 345, wherein said bad spirit, nerve or physiological disorder are atypical depressions.

347. the method for claim 345, wherein said bad spirit, nerve or physiological disorder are weight increase or disease of eating too much at one meal.

348. the method for claim 345, wherein said bad spirit, nerve or physiological disorder are drowsiness or tired.

In 349. each method among the claim 340-348, wherein said method also are included in during the very first time that μ and/or delta opiate receptor antagonist and AVP agonist is co-administered, its use half life and use between during ratio be not more than 1/2.

350. each method among the claim 340-349, wherein with use the relevant very first time at every turn during in neither use μ and/or delta opiate receptor antagonist is not used the AVP receptor stimulating agent yet.

351. each method among the claim 340-350, wherein AVP receptor stimulating agent and/or AVP receptor stimulating agent one or more with use the second relevant time durations at every turn in use.

352. the method for claim 351, wherein said AVP receptor stimulating agent are selected from down group one or more: felypressin, Desmopressin and their pharmaceutically useful salt, analog and derivant.

353. each method among the claim 340-352, the downward modulation of wherein said AVP system has produced the treatment benefit to bad spirit, nerve or physiological disorder with AVP receptor negative correlation.

354. each method among the claim 1-127, wherein said method are used for the treatment of or dispose bad spirit, nerve or physiological disorder among the patient, described bad spirit, nerve or physiological disorder are relevant with the receptor of described acceptor type.

355. the method for claim 354, wherein said disease are mood disorders, eating disorders, pain obstacle, psychoactive substance abuse, anxiety disorder or obsession.

356. each method among the claim 1-353, wherein said method is used for the treatment of or disposes the disease relevant with immune system bad among the patient who needs it, the described disease relevant with immune system and the receptor of described acceptor type are correlated with, and described method causes immune rise.

357. the method for claim 356, wherein said neurotransmitter system is an endogenous endorphins system, and described acceptor type is a delta opiate receptor, and described part is a delta opiate receptor antagonist.

358. each method among the claim 356-357, the wherein said bad disease relevant with immune system is cancer.

359. each method among the claim 356-357, the wherein said bad disease relevant with immune system is cancer, and described cancer has the cancerous cell of essentially no ζ receptor.

360. each method among the claim 356-357, the wherein said bad disease relevant with immune system be autoimmune disease, innate immunity defective, because immunodeficiency or the acquired immunodeficiency that immunosuppressant treatment causes.

361. each method among the claim 356-357, wherein said autoimmune disease is selected from down group: rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Addison's disease, ALS (Lou Gehrig disease), Alzheimer, ankylosing spondylitis, the autism spectrum disorder, autoimmune hemolytic anemia, autoimmune progesterone dermatitis, Behcet, celiac disease, the chronic fatigue syndrome, Qiu-Shi syndrome (allergic granulomatosis), the CREST syndrome, clone disease, dermatomyositis, diabetes, emphysema (COPD), endometriosis, fibromyalgia, Gourde(G) Paasche Che Shi disease, Graves disease, chronic lymphocytic thyroiditis, between the granulomatous dermatitis of matter, irritable bowel syndrome (IBS), mixed connective tissue disease, the connective tissue disease relevant with autoimmune, myasthenia gravis, parkinson, pemphigoid, pernicious anemia, primary lateral sclerosis (PLS), polychondritis (recurrent), polymyalgia rheumatica, polymyositis, psoriasis, sarcoidosis, scleroderma, siogren's syndrome, transverse myelitis, ulcerative colitis, vasculitis, Wei Genashi granulomatosis and course of infection, use vaccine or environment reaction and the autoimmune disease of secondary.

362. each method among the claim 356-357, the wherein said bad disease relevant with immune system are to infect.

363. each method among the claim 356-357, wherein said method are used to reduce microorganism of infected property or viral institute possibility of infection.

364. the method for claim 363, wherein said method are used for reducing by antibacterial, virus, fungus, parasite, Mycobacterium, yeast, chlamydiaceae, protozoacide, anthelmintic or rickettsia institute possibility of infection.

365. each method among the claim 356-357, the wherein said disease relevant with immune system is using of vaccine, and immune rise causes production of antibodies to increase, and described antibody is at the material of described vaccine institute targeting.

366. each method among the claim 1-353, wherein said method is used in needs treatments or disposes the cardiovascular diseases or patient's treatment of the disease relevant with lipid or cholesterol metabolism or dispose described disease or disease, and described cardiovascular diseases or the disease relevant with lipid or cholesterol metabolism and the receptor of described acceptor type are correlated with.

367. the method for claim 366, wherein said cardiovascular disorder or the disease relevant with lipid or cholesterol metabolism are cardiovascular disorders.

368. the method for claim 366, wherein said cardiovascular disorder or the disease relevant with lipid or cholesterol metabolism are hypertriglyceridemia, hypercholesterolemia or because the lipodystrophy that the HIV infection causes.

369. each method among the claim 1-127, wherein said method are used for the treatment of or dispose preparation deficiency to the sports in future.

370. each method among the claim 1-127, wherein said method are used for the treatment of bad spirit, nerve or physiological disorder among the patient, described bad spirit, nerve or physiological disorder are relevant with the receptor of described acceptor type.

The bad disease that 371. each method among the claim 1-353, wherein said method are used for the treatment of or disposal is relevant with the Sirt1 approach.

372. the method for claim 371, wherein said method is used for the treatment of disease relevant with aging among the patient.

373. the method for claim 371, wherein said method are selected from down group one or more: lipid metabolism, inflammation, cancer, arthritis, heart disease and neural degeneration.

374. each method among the claim 371-373, wherein said method is as the preventive measure at the physiological change that is caused by aging.