CN111135170A

CN111135170A - Use of bulleyaconitine A compound in treating psychological dependence of addictive substance

Info

Publication number: CN111135170A
Application number: CN202010076570.4A
Authority: CN
Inventors: 王永祥; 赵梦静
Original assignee: Shanghai Jiaotong University
Current assignee: Shanghai Jiaotong University
Priority date: 2020-01-23
Filing date: 2020-01-23
Publication date: 2020-05-12

Abstract

The invention provides application of an bulleyaconitine A compound in treating psychological dependence on addictive substances, and particularly discloses the use of the bulleyaconitine A compound or pharmaceutically acceptable salts thereof in (a) preventing and/or treating psychological dependence on the addictive substances; (b) reducing psychological dependence drug addiction of drugs susceptible to addiction; and/or (c) reducing the chance of a subject who has successfully abstained from the drug taking drug again (or re-using) the addictive substance. Experiments prove that the bulleyaconitine A compound can effectively treat the psychological dependence effect generated by addiction substances such as morphine, alcohol and the like, reduce the probability of relapse of the addiction substances of drug-addicts and help the drug-addicts to get rid of addiction completely.

Description

Use of bulleyaconitine A compound in treating psychological dependence of addictive substance

Technical Field

The invention belongs to the technical field of medicines, and relates to an application of an bulleyaconitine A compound in treating psychological dependence of addictive substances.

Background

At present, addiction caused by various drugs or medicines is becoming a more and more urgent problem to be solved. The addiction mainly comprises addiction caused by drugs, addiction caused by drugs easy to be addicted, and alcohol addiction.

In the case of an addict, when the addict is not taken, strong physical discomfort such as lacrimation, chills, keloids in chickens, vomiting, diarrhea, abdominal pain, tremor, etc. occurs, thereby causing physical dependence on the addict (i.e., physical dependence type addiction). Therefore, in drug rehabilitation or withdrawal treatment of an addict, some withdrawal drugs or means are often used to eliminate the physical dependence on the addict substance against such strong physical discomfort.

For example, current methods for treating physical dependence caused by opioids include: (a) replacement therapy, methadone replacement is the most commonly used first choice for drug rehabilitation at home and abroad at present; (b) rapid detoxification therapy with the opioid receptor antagonist naltrexone or naloxone to promote withdrawal; (c) non-opioid therapy, clonidine and lofexidine (Cuthill et al, 1990), can significantly inhibit withdrawal symptoms.

However, although these drugs for eliminating physical dependence on addictive substances may cause the addictive subject to no longer exhibit physiological discomfort (e.g., chills, keloids, vomiting, tremor, etc.) upon withdrawal of the addictive substance, studies have shown that these drugs do not reduce mental (or psychological) dependence in the addictive subject.

In summary, the current approaches and approaches to the solution of opioid and alcohol addiction are still limited, especially with respect to withdrawal from mental dependence, resulting in subjects in need thereof still craving for addictive substances after withdrawal from physical dependence, eventually leading to repeated use and addiction.

Therefore, there is an urgent need in the art to develop drugs for treating mental dependence on addictive substances.

Disclosure of Invention

The object of the present invention is to provide a drug which is effective in treating mental dependence on an addictive substance.

In a first aspect of the present invention, there is provided a use of an bulleyaconitine compound or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for:

(a) preventing and/or treating psychological dependence on addictive substances;

(b) reducing psychological dependence drug addiction of drugs susceptible to addiction; and/or

(c) Reducing the probability that a subject who has been successfully abstained will relapse (or reuse) an addictive substance;

wherein the bulleyaconitine A compound is selected from the following groups: bulleyaconitine A, lappaconitine A, Aconitine (Aconitine), 3-acetyl Aconitine (3-acetyl Aconitine), or their combination;

the addictive substance is selected from the group consisting of: opioids, alcohols, or combinations thereof;

the drug easy to addiction is selected from the following groups: an opioid.

In another preferred embodiment, the addictive substance is selected from the group consisting of: morphine, heroin, cannabis, meperidine, cocaine, hydromorphine, methadone, meperidine, codeine, oxycodone, levorphanol, propoxyphene, fentanyl, endorphin, enkephalin, alcohol, methamphetamine, ecstasy, ketamine, caffeine, triazolam, buprenorphine, diazepam, or combinations thereof.

In another preferred embodiment, the opioid is selected from the group consisting of: morphine, hydromorphine, fentanyl, meperidine, diacetylmorphine, oxycodone, or combinations thereof.

In another preferred embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

In another alternative, the pharmaceutical composition is in a dosage form selected from the group consisting of: oral preparation, injection, and spray.

In another preferred embodiment, the dosage form of the pharmaceutical composition may be administered by a route selected from the group consisting of: oral administration, injection (subcutaneous, intramuscular, intravenous), transdermal administration and intraperitoneal administration.

In another preferred embodiment, the subject to which the pharmaceutical composition is administered is a subject satisfying the following conditions: the subject has been treated for physical dependence withdrawal or alcohol withdrawal, such that the physical dependence has been eliminated for the addictive substance.

In another preferred embodiment, the pharmaceutical composition is administered to a subject who has been treated for physical dependence abstinence or alcohol withdrawal, such that the physical dependence has been eliminated for the addictive substance.

In another preferred embodiment, the phrase "physical dependence on the addictive substance has been eliminated" means that the subject does not experience the severe physiological reactions and symptoms associated with withdrawal when the administration of the addictive substance is discontinued.

In another preferred embodiment, said "acute physiological response and symptoms associated with withdrawal" is selected from the group consisting of: sweating, lacrimation, yawning, chills, keloid in the skin of the chicken, mydriasis, vomiting, diarrhea, abdominal pain, increased heart rate, increased blood pressure, insomnia, and tremor.

In another preferred embodiment, the pharmaceutical composition is administered to a mammal (e.g., a human) that has been treated for withdrawal of drugs and has eliminated physical dependence on addictive substances but has psychological dependence on addictive substances.

In another preferred embodiment, the pharmaceutical composition is administered to a mammal (e.g., a human) that has been treated for withdrawal and has eliminated physical dependence on addictive substances and eliminated psychological dependence on addictive substances.

In a second aspect of the invention, there is provided a pharmaceutical composition comprising:

(a) a first active ingredient, said first active ingredient being an opioid;

(b) a second active ingredient which is an bulleyaconitine compound or a pharmaceutically acceptable salt thereof, wherein the bulleyaconitine compound is selected from the following groups: bulleyaconitine A, Lappaconitine A, Aconitine (Aconitine), 3-acetyl Aconitine (3-acetyl Aconitine), or their combination; and

(c) a pharmaceutically acceptable carrier.

In a third aspect of the invention, there is provided a kit comprising:

(i) a first pharmaceutical composition comprising (a1) a first active ingredient and (a2) a pharmaceutically acceptable carrier, wherein said first active ingredient is an opioid;

(ii) a second pharmaceutical composition comprising (b1) a second active ingredient and (b2) a pharmaceutically acceptable carrier, wherein the second active ingredient is an bulleyaconitine compound, or a pharmaceutically acceptable salt thereof, wherein the bulleyaconitine compound is selected from the group consisting of: bulleyaconitine A, Lappaconitine A, Aconitine (Aconitine), 3-acetyl Aconitine (3-acetyl Aconitine), or their combination.

In another preferred embodiment, the first pharmaceutical composition and the second pharmaceutical composition are independent of each other.

In another preferred embodiment, the first pharmaceutical composition and the second pharmaceutical composition are located in separate containers.

In a fourth aspect of the invention there is provided the use of a pharmaceutical composition according to the second aspect of the invention or a kit according to the third aspect of the invention in the manufacture of a medicament or therapeutic product for reducing or eliminating the side effects or risk of psychotropic drug addiction as a result of an otherwise addictive opioid.

In a fifth aspect of the present invention, there is provided a method of treating psychological dependence on an addictive substance, comprising the steps of:

administering to a subject in need thereof a therapeutically effective amount of an bulleyaconitine compound, or a pharmaceutically acceptable salt thereof, wherein said bulleyaconitine compound is selected from the group consisting of: bulleyaconitine A, Lappaconitine A, Aconitine (Aconitine), 3-acetyl Aconitine (3-acetyl Aconitine), or their combination.

In another preferred embodiment, the subject is a mammal.

In another preferred embodiment, the subject is selected from the group consisting of: human, rat and mouse.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

FIG. 1 is a graph of the effect of single subcutaneous injections of bulleyaconitine A on morphine-induced conditioned site preference in mice; wherein P represents P <0.05 in the morphine group compared to the normal saline group; # denotes that P <0.05 in the morphine + bulleyaconitine A (300. mu.g/kg) group compared to the morphine group; the results show that the small dose of morphine (5mg/kg) can induce the formation of the mouse conditional position preference, and the bulleyaconitine A (300 mug/kg) can inhibit the formation of the mouse conditional position preference induced by the morphine;

FIG. 2 is a graph of the effect of lateral ventricle injection of the selective kappa-opioid receptor antagonist GNTI on conditional positional preference of bulleyaconitine A against mouse morphine; wherein P represents P <0.05 in the morphine group compared to the normal saline group; GNTI was administered, P ═ 0.07; the result shows that the bulleyaconitine A can effectively relieve the conditioned position preference of the mouse induced by morphine, and the GNTI can partially reverse the effect;

FIG. 3 is a graph of the effect of lateral ventricle injection of dynorphin antiserum on conditional positional preference of bulleyaconitine a against mouse morphine induction; wherein, P represents that P <0.05 in the morphine + bulleyaconitine A (300 ug/kg) group compared to the morphine group; # denotes that P <0.05 in the morphine + bulleyaconitine A (300. mu.g/kg) + dynorphin antiserum group compared to the morphine + bulleyaconitine A (300. mu.g/kg) group; the result shows that the bulleyaconitine A can effectively relieve the conditional position preference of the morphine-induced mice, and the dynorphin antiserum can reverse the effect;

figure 4 is a graph of the effect of lateral ventricle injection of the microglial inhibitor minocycline on the conditional positional preference of bulleyaconitine a against mouse morphine; wherein, P represents that P <0.05 in the morphine + bulleyaconitine A (300 ug/kg) group compared to the morphine group; # denotes that the P <0.05 for the morphine + bulleyaconitine A (300. mu.g/kg) + minocycline group compared to the morphine + bulleyaconitine A (300. mu.g/kg) group; the result shows that the bulleyaconitine A can effectively relieve the morphine-induced condition of mice that the minocycline prefers to reverse the effect;

FIG. 5 is a graph of the effect of continuous subcutaneous injections of bulleyaconitine A on morphine-induced conditioned place preference in mice; wherein P represents P <0.05 in the morphine group compared to the normal saline group; # denotes that P <0.05 in the morphine + bulleyaconitine A (300. mu.g/kg) group compared with the morphine group; the results show that the morphine (5mg/kg) with small dose can induce the formation of the condition position preference of the mice, and the bulleyaconitine A (300 mug/kg) can partially inhibit the formation of the condition position preference of the mice;

figure 6 is a graph of the effect of continuous subcutaneous bulleyaconitine injection on morphine-induced spontaneous activity in mice; wherein P represents P <0.05 in the morphine group compared to the normal saline group; # denotes that P <0.05 in the morphine + bulleyaconitine A (300. mu.g/kg) group compared with the morphine group; the results show that the morphine can induce the spontaneous activity of the mice at a small dose, and the bulleyaconitine A (300 mug/kg) can weaken the spontaneous activity of the mice;

FIG. 7 shows the effect of bulleyaconitine A on the expression of dynorphin gene and dynorphin protein in the morphine-induced conditional site preference mouse hippocampus and nucleus accumbens; the results show that the expression of the prodynorphin genes of the hippocampus and nucleus accumbens of the mice (P <0.05, and shown in figures 7A and 7B) and the expression of the protein of the dynorphin (P ═ 0.07, and P <0.05, and shown in figures 7C and 7D) are obviously increased after the bulleyaconitine A is administered;

FIG. 8 is a graph of the effect of bulleyaconitine A on the conditioned place preference of alcohol-induced mice; wherein, P represents P <0.05 in the alcohol group compared to the saline group; # denotes that P <0.05 in the alcohol + bulleyaconitine A (300. mu.g/kg) group compared with the alcohol group; the results show that alcohol (12g/kg) can induce the formation of conditional position preference of mice, and bulleyaconitine A (300 mug/kg) can inhibit the formation of conditional position preference of mice.

Detailed Description

The present inventors have conducted extensive and intensive studies to provide a class of compounds for preventing and/or treating mental dependence on an addictive substance through a large number of screens and tests. The inventor unexpectedly finds that the bulleyaconitine A compound has excellent effect on preventing and/or treating the psychic dependence of addicts (such as opium and alcohol). The present invention has been completed based on this finding.

Term(s) for

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….

In the present invention, the terms "physical dependence", "physical dependence" and "physiological dependence" are used interchangeably to refer to the dependence that can trigger withdrawal syndrome once the use of an addictive drug is discontinued.

In the present invention, the term "withdrawal syndrome" refers to a series of symptoms caused by the severe physiological reactions of the body, such as sweating, lacrimation, yawning, chills, keloids, mydriasis, vomiting, diarrhea, abdominal pain, increased heart rate, increased blood pressure, insomnia, tremor, etc., once the use of a patient who has developed a dependency is discontinued due to the continuous use of addictive substances.

In the present invention, the terms "psychological dependence" and "psychological dependence" are used interchangeably to refer to a patient's craving for a drug in order to obtain a particular pleasure after taking an addictive drug.

"prevention" and "treatment" as used herein include delaying and stopping the progression of the disease, or eliminating the disease, and do not require 100% inhibition, elimination, or reversal. In some embodiments, the composition or pharmaceutical composition of the invention prevents, reduces, inhibits and/or reverses an addictive substance's mental dependence, e.g., by at least about 10%, at least about 30%, at least about 50%, or at least about 80%, as compared to the level observed in the absence of the pharmaceutical composition of the invention.

In the present invention, the term "relapse" refers to the repeated use of an addictive substance. The mode of resorption is not limited, for example (but not limited to): suction, oral administration, injection, etc.

Active ingredient

As used herein, "active ingredient of the present invention" refers to said bulleyaconitine compound or a pharmaceutically acceptable salt thereof. Representative active ingredients of the present invention include (but are not limited to): bulleyaconitine A, lappaconitine A, Aconitine 3-acetyl Aconitine, or their combination;

the active ingredient, the pharmaceutical composition containing the active ingredient, the medicine box and other products can obviously reduce or eliminate the side effect or risk of psychological dependence drug addiction caused by the opioid drug which is easy to be addicted.

The active ingredients of the present invention may be amorphous, crystalline or mixtures thereof.

As used herein, "pharmaceutically acceptable salt" refers to a salt formed by a compound of the active ingredient of the present invention with an acid or a base, which is suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed between the compounds of the active ingredients of the present invention and an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid. One preferred class of salts is that formed by reacting a compound of the active ingredient of the invention with a base. Suitable bases for salt formation include, but are not limited to: inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and sodium phosphate, and organic bases such as ammonia, triethylamine and diethylamine.

The active ingredients of the present invention may be artificially synthesized or extracted, for example, extracts containing the active ingredients of the present invention.

Pharmaceutical composition

The present invention also provides a pharmaceutical composition comprising a safe and effective amount of an active ingredient. The pharmaceutical composition can effectively treat psychological dependence caused by addictive substances such as morphine, alcohol and the like.

As used herein, the term "safe and effective amount" refers to: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of the active ingredient/dose of the present invention, more preferably, 10-500mg of the active ingredient/dose of the present invention. Preferably, the "one dose" is a capsule, tablet, injection, etc.

In the present invention, the "pharmaceutically acceptable carrier" means: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with the active ingredient without significantly diminishing the efficacy of the active ingredient.

In the pharmaceutical composition of the present invention, the administration mode of the active ingredient is not particularly limited, and representative administration modes include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be delayed in a certain portion of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active ingredient may also be in microencapsulated form with one or more of the above excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.

In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms of the active ingredients of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

In the pharmaceutical compositions of the invention, the general range of therapeutically effective dosages of the active ingredients will be: about 1 to 2000 mg/day, about 10 to about 1000 mg/day, about 10 to about 500 mg/day, about 10 to about 250 mg/day, about 10 to about 100 mg/day, or about 10 to about 80 mg/day. A therapeutically effective dose will be administered in one or more doses. It will be understood, however, that the specific dose of the active ingredients of the invention for any particular patient will depend upon a variety of factors such as the age, sex, body weight, general health, diet, individual response, time of administration, severity of the condition to be treated, dosage form, mode of application and concomitant drug(s). A therapeutically effective amount for a given situation can be determined using routine experimentation and is within the ability and judgment of the clinician or physician. In any event, the active ingredient will be administered in multiple doses based on the individual condition of the patient and in a manner that allows for the delivery of a therapeutically effective amount.

The main advantages of the invention include:

(a) the present invention provides a class of drugs useful for the effective treatment of mental dependence on addictive substances.

(b) The bulleyaconitine A compound has obvious treatment effect on the psychotropic dependence of addictive substances such as opium drugs, alcohol and the like, thereby reducing the psychotropic requirement of relapse through drug withdrawal and having great significance for completely withdrawing the addictive substances.

The invention is further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

General procedure

Morphine-induced mouse conditional site preference model

Conditional Positional Preference (CPP) is to place the test animal in a certain observation area of a conditional positional preference box and administer a psychotropic drug (e.g., morphine), and then observe the activity and residence time of the test animal in the black and striped areas of the conditional positional preference box. A small gate is arranged between the black area, the stripe area and the middle area for the free shuttling of animals. Each time the animal is in the administration area, the animal will make the black area and the striated area preferred under the action of the reward effect of the drug, and the degree of the preference is related to the mental dependence of the drug. CPP is a classical experimental model for the evaluation of drug dependence.

Example 1 Single subcutaneous injection of bulleyaconitine A (BAA) effectively relieves morphine-induced conditioned place preference in mice

Male kunmin mice (weighing 18-22g) were acclimatized for 3 days, followed by palpation of the mice for 3 days, twice daily, 2 minutes each, for convenient subsequent dosing. The mice were randomly divided into four groups, namely a normal saline group, a morphine-tolerant group, a bulleyaconitine A group (300 mug/kg) and a morphine-tolerant + bulleyaconitine A group (300 mug/kg), and 10 mice were each group.

Establishing conditional location preferences: the experiment was performed for a total of 6 days.

On day 0, four groups of mice are respectively placed into three boxes with preferred condition positions, the baffle plates are removed, the mice are allowed to freely shuttle for 15 minutes, the residence time of the mice in the black box and the stripe box is recorded, and the mice staying in any box for more than 450s are removed. Because the residence time of the stripe box is shorter than that of the black box, the stripe box is selected as a medicine accompanying box.

On

days

1,3 and 5, 8:00 in the morning, the morphine-tolerant group and the morphine-tolerant + bulleyaconitine A group (300 mug/kg) are injected with morphine subcutaneously (5mg/kg), the normal saline group is injected with normal saline with the same quantity subcutaneously, the bulleyaconitine A group (300 mug/kg) is injected subcutaneously and put into a striping box, a baffle is closed, and training (namely putting into the striping box to lead the bulleyaconitine A group to move freely) is carried out for 40 minutes; in 4:00 pm, four groups were given physiological saline, placed in a black box, closed, and trained for 40 minutes.

On

days

2 and 4, 8:00 in the morning, four groups are respectively given with physiological saline, put into a black box, close a baffle and train for 40 minutes; 4:00 in the afternoon, the morphine-tolerant group and the morphine-tolerant + bulleyaconitine A group (300 mug/kg) are injected with morphine subcutaneously (5mg/kg), the normal saline group is injected with normal saline with the same quantity subcutaneously, the bulleyaconitine A group (300 mug/kg) is injected with bulleyaconitine A (300 mug/kg) subcutaneously and put into a striping box, the baffle is closed, and training is carried out for 40 minutes.

On day 6, 8:00 in the morning, the morphine-resistant + bulleyaconitine group (300. mu.g/kg) was injected subcutaneously with bulleyaconitine A (300. mu.g/kg), saline group, bulleyaconitine A group (300. mu.g/kg) and morphine-resistant group with the same amount of saline. And 8:50, respectively placing the four groups of mice into a condition position preference box, removing the baffle, enabling the mice to freely shuttle, and recording the residence time of the mice in the stripe box and the black box.

The results are shown in fig. 1, compared with the normal saline group and the bulleyaconitine A group (300 mug/kg), the morphine-dependent group mice have obvious preference (P <0.05) for the striated box, while the morphine-tolerant group plus the bulleyaconitine A group (300 mug/kg) has obviously weakened preference (P <0.05) for the striated box, which indicates that the bulleyaconitine A can effectively relieve the conditioned position preference of the mice induced by morphine.

Example 2 lateral ventricle injection of a Selective kappa-opioid receptor antagonist GNTI reverses the Effect of bulleyaconitine A on the conditional site bias induced by mouse morphine

Morphine-induced conditional positional preference was established substantially as in example 1, except that the species, dose and mode of administration of each group of mice were as described in this example. The experiment was divided into 4 groups, which were morphine-tolerant, morphine-tolerant + GNTI, morphine-tolerant + bulleyaconitine a (300 μ g/kg) treatment and morphine-tolerant + bulleyaconitine a (300 μ g/kg) + GNTI, each group containing 10 animals.

The day after the establishment of the conditional site preference, four groups of mice were subjected to lateral ventricle intubation as in example 2: lateral ventricle intubation: male Kunming mice (weighing 18-22g) were acclimated for 3 days.Mice were anesthetized with 1.5% sodium pentobarbital (5ml/kg, i.p.). The mouse is horizontally fixed on a stereotaxic instrument, the breathing is kept uniform, the head is horizontal, and the mouse cannot be shaken. Shearing hair at the middle operative field of skull, wiping with alcohol cotton ball, cutting a small opening (0.5-1cm) with scissors using the connection line of left and right cochlea as baseline and the middle of skull as axis, wiping off a small amount of blood, and dipping with appropriate amount of 5% H₂O₂The skull cap is slightly wiped to find the bregma point, the position of the catheter is determined, the bregma point is 0.7mm backwards and 1mm leftwards, a small hole with the depth of 2.5mm is drilled, and the hole is lightly drilled, so that the dura mater is not injured as much as possible, and bleeding is avoided. The outer tube is slowly inserted into the drilled hole, a proper amount of erythromycin is coated on the wound surface, the sleeve is fixed by dental cement (the solvent and the powder are mixed in proportion), and the setting time is 10 minutes. The mice are raised in a single cage after waking up, the mice generally need to be rested for 3 days until surgical stress disappears, the damaged blood brain barrier is recovered, and the mice are habituated to be touched in the process of restitution, so that the mice are convenient to subsequently administer the medicine. On day 6 of the establishment of conditional positional preference, 8:00 a.m., 5 μ l of physiological saline was injected into the lateral ventricle of mice in the morphine-tolerant group and the morphine-tolerant + bulleyaconitine A group (300 μ g/kg), and GNTI (5 μ g) was administered to the lateral ventricle of mice in the morphine-tolerant + GNTI group and the morphine-tolerant + bulleyaconitine A group (300 μ g/kg) + GNTI group. After one hour, four groups of mice were placed in the condition position preference boxes, respectively, the baffles were removed, the mice shuttled freely, and the residence times of the mice in the stripe box and the black box were recorded.

As shown in fig. 2, the morphine-dependent mice had a significant preference for the striated box, while the administration of GNTI alone had no effect on the development of the conditioned place preference of morphine-induced mice, whereas the morphine-tolerant + bulleyaconitine a (300 μ g/kg) group had a significantly reduced preference for the striated box (P <0.05), while the mice had a significantly restored preference for the striated box after the administration of GNTI (P0.09), indicating that GNTI could partially reverse the conditioned place preference of bulleyaconitine against mouse morphine induction.

Example 3 Reversal of conditional site preference induced by Aconitum kusnezoffii A in mice by injecting dynorphin antiserum into lateral ventricle

Morphine-induced conditional positional preference was established substantially as in example 1, except that the species, dose and mode of administration of each group of mice were as described in this example. The experiment is divided into 4 groups, namely a morphine tolerance group, a morphine tolerance and dynorphin antiserum group, a morphine tolerance and bulleyaconitine A group (300 mu g/kg) treatment group and a morphine tolerance and bulleyaconitine A (300 mu g/kg) and dynorphin antiserum group, wherein 10 morphine antibodies are used in each group.

The day after the establishment of the conditional site preference, four groups of mice were subjected to lateral ventricle intubation as in example 2. On day 6 of the establishment of conditional site preference, 8:00 a.m., mice in the morphine-tolerant group and the morphine-tolerant + bulleyaconitine a group (300 μ g/kg) were injected with physiological saline (5 μ l) into the lateral ventricle of the mice in the morphine-tolerant + dynorphin antiserum group and the morphine-tolerant + bulleyaconitine a group (300 μ g/kg) + dynorphin antiserum group were administered with dynorphin antiserum (1:30) into the lateral ventricle of the mice in the dynorphin antiserum group. After one hour, four groups of mice were placed in the condition position preference boxes, respectively, the baffles were removed, the mice shuttled freely, and the residence times of the mice in the stripe box and the black box were recorded.

The results are shown in fig. 3, the morphine-dependent mice had significant preference for the striation box, the separate administration of dynorphin antiserum had no effect on the formation of the conditioned place preference of morphine-induced mice, while the preference of morphine-tolerant + bulleyaconitine a (300 μ g/kg) group for the striation box was significantly reduced (P <0.05), and the preference of mice for the striation box was significantly restored (P <0.05) after the administration of dynorphin antiserum, indicating that the conditional place preference of bulleyaconitine-induced mice was reversed by the dynorphin antiserum.

Example 4 lateral ventricle injection of the microglial inhibitor minocycline Reversal Aconitine Effect against mouse morphine-induced conditioned site preference

Morphine-induced conditional positional preference was established substantially as in example 1, except that the species, dose and mode of administration of each group of mice were as described in this example. The experiment is divided into 4 groups, namely a morphine tolerance group, a morphine tolerance + minocycline group, a morphine tolerance + bulleyaconitine A group (300 mug/kg) treatment group and a morphine tolerance + bulleyaconitine A group (300 mug/kg) + minocycline group, wherein each group comprises 10 animals.

The day after the establishment of the conditional site preference, four groups of mice were subjected to lateral ventricle intubation as in example 2. On day 6 of the set of conditional site preferences, 8:00 morning, mice in the morphine tolerant group and morphine tolerant + bulleyaconitine A group (300. mu.g/kg) treatment group were injected lateral ventricles with physiological saline (5. mu.l), mice in the morphine tolerant + minocycline group and morphine tolerant + bulleyaconitine A group (300. mu.g/kg) + minocycline group were given lateral ventricles with minocycline (10. mu.g). After one hour, four groups of mice were placed in the condition position preference boxes, respectively, the baffles were removed, the mice shuttled freely, and the residence times of the mice in the stripe box and the black box were recorded.

The results are shown in fig. 4, where morphine-dependent mice had a significant preference for the striated box, minocycline alone had no effect on the development of the conditioned place preference of morphine-induced mice, whereas morphine-tolerant + bulleyaconitine a (300 μ g/kg) group had a significantly reduced preference for the striated box (P <0.05), whereas after minocycline administration the preference for the striated box was significantly restored (P <0.05), indicating that minocycline could reverse the conditioned place preference of bulleyaconitine against mouse morphine-induced.

Example 5 continuous subcutaneous injection of bulleyaconitine A inhibits morphine-induced conditioned site preference in mice

Establishing conditional location preferences: the experiment was performed for a total of 6 days. On day 0, four groups of mice are respectively placed into three boxes with preferred condition positions, the baffle plates are removed, the mice are allowed to freely shuttle for 15 minutes, the residence time of the mice in the black box and the stripe box is recorded, and the mice staying in any box for more than 450s are removed. Because the residence time of the stripe box is shorter than that of the black box, the stripe box is selected as a medicine accompanying box. On days 1,3 and 5, 8:00 in the morning, subcutaneously injecting bulleyaconitine A (300 mug/kg) into a morphine tolerance group and a bulleyaconitine A group (300 mug/kg), administering the same amount of normal saline into a normal saline group, a morphine tolerance group and a bulleyaconitine A group (300 mug/kg), subcutaneously injecting morphine (5mg/kg) into the morphine tolerance group and the morphine tolerance group (300 mug/kg) after 40 minutes, subcutaneously injecting the same amount of normal saline into the normal saline group, subcutaneously injecting the bulleyaconitine A (300 mug/kg) into the bulleyaconitine A group (300 mug/kg) into a stripe box, closing a baffle, and training for 40 minutes; in the afternoon, 4:00 and 4:40, four groups are respectively given with physiological saline, put into a black box, close a baffle and train for 40 minutes; on days 2 and 4, 8:00 and 8:40 in the morning, respectively adding physiological saline into four groups, placing the four groups into a black box, closing a baffle, and training for 40 minutes; at 4:00 pm, the morphine tolerance group and the bulleyaconitine A group (300 mug/kg) are injected with bulleyaconitine A (300 mug/kg) subcutaneously, the normal saline group, the morphine tolerance group and the bulleyaconitine A group (300 mug/kg) are given with the same amount of normal saline, after 40 minutes, the morphine tolerance group and the bulleyaconitine A group (300 mug/kg) are injected with morphine (5mg/kg) subcutaneously, the normal saline group is injected with the same amount of normal saline subcutaneously, and the bulleyaconitine A group (300 mug/kg) is injected with bulleyaconitine A (300 mug/kg) subcutaneously and placed in a striping box, a baffle is closed, and training is carried out for 40 minutes. Day 6, 8:00 am, the baffles were removed and the mice shuttled freely and their residence times in the striped box and black box were recorded.

The results are shown in fig. 5, and compared with the normal saline group and the bulleyaconitine group (300 μ g/kg), the morphine-dependent mice have obvious preference (P <0.05) for the striated box, while the morphine-resistant + bulleyaconitine group (300 μ g/kg) has obviously weakened preference (P <0.05) for the striated box, which indicates that the bulleyaconitine can inhibit the formation of the conditional position preference of the morphine-dependent mice.

Example 6 continuous subcutaneous injection of bulleyaconitine A is effective in attenuating morphine-induced spontaneous activity in mice

The experiment was performed for a total of 5 days. According to example 1, it is known that mice have a certain natural preference for the black box, so the striped box is selected to detect its path of movement. The continuous day of 5 days, 8:00 in the morning, the morphine-tolerant group and the bulleyaconitine group (300 mug/kg) were subcutaneously injected with bulleyaconitine A (300 mug/kg), the normal saline group, the morphine-tolerant group and the bulleyaconitine A group (300 mug/kg) were administered with the same amount of normal saline, after 40 minutes, the morphine-tolerant group and the bulleyaconitine A group (300 mug/kg) were subcutaneously injected with morphine (5mg/kg), the normal saline group was subcutaneously injected with the same amount of normal saline, the bulleyaconitine A group (300 mug/kg) was subcutaneously injected with bulleyaconitine A (300 mug/kg) and placed in a striping box, the baffle was closed, and the distance of the mouse moving in the striping box for 30 minutes.

The results are shown in fig. 6, in which the morphine-dependent mice exhibited vigorous locomotion and significantly increased locomotion distance (P <0.05) compared to the saline group and the bulleyaconitine a (300 μ g/kg) group, whereas the morphine-resistant + bulleyaconitine a (300 μ g/kg) group exhibited significantly decreased locomotion activity on day 3 until day 5, which was equal to the saline group (P < 0.05).

Example 7 Effect of bulleyaconitine A on morphine-induced conditioned site preference of Hippocampus and nucleus accumbens dynorphin gene and protein expression in mice

Male kunmin mice (weighing 18-22g) were acclimatized for 3 days, followed by palpation of the mice for 3 days, twice daily, 2 minutes each, for convenient subsequent dosing.

Morphine-induced conditional positional preference was established substantially as in example 1, except that the species, dose and mode of administration of each group of mice were as described in this example. The mice were randomly divided into four groups, namely a normal saline group, a bulleyaconitine A (300 mug/kg) group, a morphine-tolerant + bulleyaconitine A (300 mug/kg) group, and 10 mice in each group.

On day 6 when the conditional site preference was established, after 1 hour of administration of BAA or physiological saline, the mice were sacrificed, and the hippocampus of the brain and nucleus accumbens of the mice were taken to detect the expression of the pro-dynorphin gene.

The results are shown in fig. 7, and compared with morphine-tolerant mice, the expression of the dynorphin gene (fig. a and B) and the expression of dynorphin protein (fig. C and D) in the hippocampus and nucleus accumbens of the mice are obviously improved after bulleyaconitine A is administered.

Example 8 bulleyaconitine A inhibits alcohol-induced conditioned place preference in mice

Male kunmin mice (weighing 18-22g) were acclimatized for 3 days, followed by palpation of the mice for 3 days, twice daily, 2 minutes each, for convenient subsequent dosing. The mice were randomly divided into four groups, namely a normal saline group, an alcohol-dependent group, a bulleyaconitine A group (300 mug/kg) and an alcohol-dependent + bulleyaconitine A group (300 mug/kg), and 10 mice were each group.

Establishing conditional location preferences: the experiment was performed for a total of 14 days. On day 0, four groups of mice are respectively placed into three boxes with preferred condition positions, the baffle plates are removed, the mice are allowed to freely shuttle for 15 minutes, the residence time of the mice in the black box and the stripe box is recorded, and the mice staying in any box for more than 450s are removed. Because the residence time of the stripe box is shorter than that of the black box, the stripe box is selected as a medicine accompanying box. On days 1,3, 5, 7, 9, 11 and 13, 8:00 in the morning, subcutaneously injecting bulleyaconitine A (300 mug/kg) in an alcohol dependence + bulleyaconitine A group (300 mug/kg), and administering the same amount of normal saline in a normal saline group, an alcohol dependence group and a bulleyaconitine A group (300 mug/kg), injecting alcohol (12g/kg) in the abdominal cavity after 40 minutes, subcutaneously injecting the same amount of normal saline in a normal saline group, and subcutaneously injecting bulleyaconitine A (300 mug/kg) in a bulleyaconitine A group (300 mug/kg) to a striping box, closing a baffle, and training for 30 minutes; in the afternoon, 4:00 and 4:40, four groups are respectively given with physiological saline, put into a black box, close a baffle and train for 30 minutes; on days 2,4, 6, 8, 10, 12 and 14, 8:00 and 8:40 in the morning, respectively adding physiological saline into four groups, placing the four groups into a black box, closing a baffle, and training for 30 minutes; at 4:00 pm, subcutaneously injecting bulleyaconitine A (300 mug/kg) into an alcohol dependence and bulleyaconitine A group (300 mug/kg), administering the same amount of normal saline into a normal saline group, the alcohol dependence group and the bulleyaconitine A group (300 mug/kg), injecting alcohol (12g/kg) into the abdominal cavity of the alcohol dependence group and the alcohol dependence and bulleyaconitine A group (300 mug/kg) after 40 minutes, subcutaneously injecting the same amount of normal saline into the normal saline group, placing the bulleyaconitine A group (300 mug/kg) subcutaneously injecting the bulleyaconitine A (300 mug/kg) into a striping box, closing a baffle, and training for 30 minutes. Day 15, 8:00 am, the baffles were removed and the mice shuttled freely and their residence times in the striped box and black box were recorded.

The results are shown in fig. 8, compared with the normal saline group and the bulleyaconitine A group (300 μ g/kg), the alcohol-dependent group mice have obvious preference (P <0.05) for the striped box, and the alcohol-dependent + bulleyaconitine A group (300 μ g/kg) has obviously weakened preference (P <0.05) for the striped box, which indicates that the bulleyaconitine A can inhibit the formation of the conditioned place preference of the alcohol-dependent mice.

Discussion of the related Art

Addiction drug dependence is a chronic recurrent brain disease, which is mainly characterized by the compulsive drug use behavior and the uncontrollable drug amount of the addiction drug. The opioid drug includes morphine, heroin, methadone, dolantin, fentanyl, etc. Morphine, a typical representative of opioids, produces central analgesia, mainly by agonizing the μ -opioid receptors, blocking pain transduction. However, if opioid is used for a long time or repeatedly, the organism can be tolerant and dependent on the opioid, so that opioid is both drug and drug, and the addiction of opioid is a health and social problem which needs to be solved urgently in the world.

Opioid addiction, which is the cumulative result of dependence and tolerance, mainly involves both physical (physiological) and mental (psychological) dependence. Physical dependence is repeated to avoid withdrawal symptoms, and the dosage is gradually increased and the frequency of administration is gradually increased (Nestler et al, 1993).

The mental dependence refers to the craving of psychological drug-seeking of the depended and the euphoria achieved by repeated drug-seeking, and is expressed as a reward effect, and the mental dependence is not easy to eliminate, so that the patient is prompted to repeat the drug-seeking frequently.

Alcohol is a psychoactive substance with high addictive properties. Global alcohol dependence reaches 1.4 billion, and its abuse and dependence bring serious adverse effects and economic burden to the individual and society. About 330 million people die each year worldwide due to excessive use of alcohol. The harmful use of alcohol can also cause diseases such as alcoholic liver, liver cirrhosis and the like. Alcohol abuse, addiction has become a serious public health disaster and a worldwide problem endangering human health, being the third global public health problem after cardiovascular diseases and tumors (crabe et al, 2003). Studies have reported approximately 1/3 populations in western countries as potential alcohol-dependent patients, 10% of which are heavy drinkers and 5% of which are problem drinkers. Although the problem of alcohol tumor formation in China is not as serious as that in western countries, the wine yield and the per capita consumption are obviously increased along with the economic development of the recent 20 years. A plurality of national or regional alcohol drinking epidemiological surveys in China show that the alcohol consumption in China is increasing dramatically from the eighties of the twentieth century, various problems caused by excessive alcohol drinking are increasing continuously, and the alcohol drinking rates of men, women and the whole year are respectively increased to 74.9%, 38.8% and 59.0%.

Kappa-opioid receptors are widely distributed in the brain and regulate various neurotransmitter systems. It is present in the midbrain Ventral Tegmental Area (VTA), nucleus accumbens (NAc), dorsal striatum, prefrontal cortex (PFC), Locus Coeruleus (LC), amygdala, etc., and is closely related to emotional, cognitive and motivational behaviors, etc. Numerous studies have shown that kappa-opioid receptor agonists, under certain conditions, can reduce drug abuse behavior (Morani et al, 2009; rudi-Bettschen et al, 2010), reduce drug foraging behavior and drug accumulation. For example, k-opioid receptor agonists, U69,593, when used in combination with fentanyl, attenuate self-administration of monkey fentanyl (Negus et al, 2008), k-opioid receptor agonists, sage refiners, and attenuate self-administration of remifentanil and cocaine (Freeman et al, 2014). On the other hand, there have been several studies showing that drug relapse and alcohol seeking can be inhibited by using kappa opioid receptor antagonists. For example, pre-administration of the kappa-opioid receptor antagonist nor-BNI can block the foraging behavior of mice to cocaine (Redi la and Chavkin, 2008). Dynorphin is an endogenous kappa opioid receptor agonist, is widely distributed in the brain and spinal cord, and can play an important role in the dependence formation process by activating kappa opioid receptors. Studies have shown that lateral ventricle injection of dynorphin can effectively control morphine-dependent withdrawal symptoms (Takemori et al, 1993), and reports have indicated that dynorphin expression is elevated in drug abuse and withdrawal, possibly in contradiction to previous studies (Wee and Koob, 2010). These studies suggest that dynorphin/kappa-opioid receptors may be effective targets for the treatment of drug addiction.

The psychological dependence of opiates and alcohol is mainly caused by the existence of reward system in central nervous system, and the addictive drug acts directly on the reward system in brain, finally activates the release of dopamine in brain. Where VTA and NAc are the last common path for the reward system. Normally, the dopaminergic neuron of VTA is inhibited by gamma-aminobutyric acid (GABA) interneuron, after the opiate drug is used, the receptor on the GABA interneuron is excited, the activity of the neuron is inhibited, the tensility inhibition of the GABA neuron on the dopaminergic neuron is relieved, and the release of dopamine is stimulated. Kappa-opioid receptors are distributed on gabaergic neurons of NAc and VTA, and studies have shown that agonism of kappa-opioid receptors can lead to decreased dopamine release (Karkhani s et al, 2016), and that dopamine release from VTA and NAc is significantly decreased after the use of kappa-opioid receptor agonists (Ford et al, 2006). Kappa-opioid receptor agonist U50,488H increased dopamine reuptake in mice PFC, NAc, and striatum due to activation of ERK1/2 (Ford et al, 2006). Thus, the psychotropic dependence of opiates and alcohol may be associated with the ERK signaling pathway.

The current psychic dependence on opioids is primarily some non-drug treatment. For example, pathological memory associated with clues can be effectively erased by regression after administration of a small dose of drug using a "non-conditional stimulus-regression" mode. Also, psychological treatments can help addicts reduce craving and relapse on drugs.

At present, the main medicines for treating alcohol dependence are the main medicines. Disulfiram (1949), which is an aldehyde oxidase inhibitor that causes an aversive effect after drinking wine to control the use of alcohol; naltrexone (1994), attenuates endogenous opioid-induced alcohol intake by blocking opioid receptors. Although the medicines have certain curative effect, the problems of poor medication compliance exist, and only 6 percent of alcoholics in the United states are willing to receive medication. And naltrexone is reported to damage the liver, and the exact curative effect and action mechanism of naltrexone still need further research.

Opioid addiction and alcohol addiction not only seriously harm the physical health of the addict, but also cause huge social and economic burden and seriously harm public safety. The development of new drugs is still an effective way to solve opioid addiction and alcohol addiction. Although the traditional addictive treatment medicines of methadone and cola are widely applied to clinic, the traditional addictive treatment medicines have application limit and side effects, for example, methadone has addiction risk, withdrawal phenomenon can be generated once the medicine is stopped, medicine withdrawal reaction is serious, and the treatment compliance of clonidine and lofexidine is poor. The non-drug treatment means opens up a new idea for treating the addiction of the opioid drugs, but is still in the exploration stage. Therefore, aiming at the increasingly serious problems of opioid addiction, alcohol addiction and the like, the appearance of some traditional Chinese medicine preparations brings new hopes to addicts. Aiming at patients in different drug rehabilitation stages, effective traditional Chinese medicine preparations are developed to quickly and effectively control withdrawal symptoms, reduce psychological craving and improve the level of drug dependence resistance, which is a problem to be solved urgently. Therefore, the method for further researching the methods for resisting opioid addiction and alcohol addiction has important significance.

The ranunculaceae aconitum plant is a famous Chinese herbal medicine, has a long history and is widely applied. Chinese aconitum plants have abundant resources, about 200 kinds, about 70 kinds of Chinese aconitum plants can be used as medicines, and root tubers and roots are mostly used as medicines, so that the Chinese aconitum plants have the effects of dispelling wind, removing dampness, resisting inflammation, relieving pain and the like. Diterpene alkaloids are the main chemical components of the plant of the genus wucao, and are also the most main pharmacologically active components thereof. Diterpene alkaloids can be generally classified into 4 broad categories: c18-diterpenoid alkaloid, C19-diterpenoid alkaloid, C20-diterpenoid alkaloid and diterpenoid alkaloid, wherein C19-diester alkaloid is the most discovered alkaloid at present and is relatively more researched, and bulleyaconitine A, aconitine, 3-acetyl aconitine, lappaconitine and the like are representative alkaloids.

The bulleyaconitine A is an aconitine alkaloid separated from Yunnan Siberian Dula which is a specific medicinal plant in Yunnan, has a chemical structure similar to that of aconitine and is C19 diester diterpene alkaloid, but has a difference between p-methoxybenzoyl ester groups on two hydroxyl groups at C3 and C15. Bulleyaconitine A tablet and injection are approved by the national food and drug administration in 1983 for clinical treatment of neuropathic pain, rheumatic arthralgia, cancer pain, etc. And bulleyaconitine A has the advantages of large treatment range (large drug treatment window) and small toxicity (Bello-Ramirez and Nava-Ocapo, 2004), so the bulleyaconitine A is used for treating clinical various chronic pains for thirty years (Tang et al, 1986).

Research shows that aconitine, bulleyaconitine A, lappaconitine A, aconitine A and aconitum sinomontanum A can effectively treat various chronic pains such as neuropathic pain, bone cancer pain, formalin pain and the like. The compounds mainly stimulate microglia of spinal cord dorsal horn to release endogenous dynorphin, and act on kappa-opioid receptors on glial cell-neuron postsynaptic neurons to produce analgesic effect. Further studies showed that these aconite alkaloids release dynorphin by activating the cAMP/PKA/p38 MPKA/CREB signal transduction pathway.

However, prior to the present invention, there has been no report or research that aconitine alkaloids such as bulleyaconitine A can treat psychological dependence or psychological addiction to addictive substances (e.g. morphine).

The research of the invention surprisingly proves for the first time that the bulleyaconitine A compound can effectively treat the psychological dependence effect generated by addiction substances such as morphine, alcohol and the like, reduce the probability of relapse of the addiction substances of drug-addicts and help the drug-addicts to completely get rid of addiction.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

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Claims

1. Use of an bulleyaconitine A compound or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for:

the drug easy to addiction is selected from the following groups: an opioid.

2. The use of claim 1, wherein the addictive substance is selected from the group consisting of: morphine, heroin, cannabis, meperidine, cocaine, hydromorphine, methadone, meperidine, codeine, oxycodone, levorphanol, propoxyphene, fentanyl, endorphin, enkephalin, alcohol, methamphetamine, ecstasy, ketamine, caffeine, triazolam, buprenorphine, diazepam, or combinations thereof.

3. Use according to claim 1, wherein the opioid is selected from the group consisting of: morphine, hydromorphine, fentanyl, meperidine, diacetylmorphine, oxycodone, or combinations thereof.

4. The use according to claim 1, wherein the subject to which the pharmaceutical composition is administered is a subject satisfying the following conditions: the subject has been treated for physical dependence withdrawal or alcohol withdrawal, such that the physical dependence has been eliminated for the addictive substance.

5. The use of claim 4, wherein said "physical dependence on the addictive substance has been eliminated" means that the subject does not experience the severe physiological reactions and symptoms associated with withdrawal when the administration of the addictive substance is discontinued.

6. The use of claim 5, wherein the "acute physiological response and symptoms associated with withdrawal" is selected from the group consisting of: sweating, lacrimation, yawning, chills, keloid in the skin of the chicken, mydriasis, vomiting, diarrhea, abdominal pain, increased heart rate, increased blood pressure, insomnia, and tremor.

7. A pharmaceutical composition, comprising:

(a) a first active ingredient, said first active ingredient being an opioid;

(c) a pharmaceutically acceptable carrier.

8. A kit, comprising:

9. Use of a pharmaceutical composition according to claim 7 or a kit according to claim 8 for the manufacture of a medicament or therapeutic product for reducing or eliminating the side effects or risk of psychotropic drug addiction caused by otherwise addictive opioids.

10. The use according to claim 9, wherein the subject to which the pharmaceutical composition is administered is a subject satisfying the following conditions: the subject has been treated for physical dependence withdrawal or alcohol withdrawal, such that the physical dependence has been eliminated for the addictive substance.