RU1803105C - Method for treating as dependent on opiates during the experiment - Google Patents

Abstract

The invention relates to medicine, in particular experimental medicine, and can be used to treat opiate addiction. This method allows to increase the effectiveness of treatment by obtaining an irreversible aversion. The treatment of opiate addiction is that the euphoric action of the opiate is opposed by the accompanying aversive reactions, an increase in nervous system excitation caused by strychnine group drugs, which leads to the cessation of self-administration of the habitual drug by dependent animals and the elimination of dependence on it. 3 tab.

Description

The invention relates to medicine, in particular experimental medicine, and can be used to treat opiate addiction.

An object of the invention is to increase the effectiveness of opiate dependence therapy in an experiment.

The goal is achieved in that for the formation of an aversion with respect to opiates, a preparation of the strychnine group, securinin, is used, which is used in the form of a morphine-securinine mixture containing 0.4% of the drug and at least 0.12% of analeptic and intended for self-administration by animals in individual subconvulsive doses.

Morphine and other opiates are known to be synergists of the cerebrospinal convulsant, strychnine a. Therefore, if a drug addict is saturated with this convulsive analeptic in a subconvulsive dose, then the administration of an opiate drug against this background will increase the level of

excitation, which can be expected to be accompanied by a fear effect similar to that which occurs at preconvulsive levels of excitation with pure strychnine intoxication. Such a distortion of the effect of opium poisoning can be punishing and can serve as the basis for aversive treatment of addictions.

Additional studies have found that the reaction of potentiation of strychnine excitation by morphine does not develop instantaneously, but over a period of 5-15 minutes, which is quite tolerable for people (after all, a person will receive the necessary explanations before treatment that have both purely informational and psycho therapeutic value, and will fear an aversive effect in case of violation of the regime of abstinence from the drug), but it is completely unacceptable from a technical point of view for testing on a model with self-administration of opiate in Zhyvosyl

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notable, since in this case the aversive factor (the action of the convulsant) must be precisely correlated in time with the reinforcing factor (the effect of the drug), which occurs almost immediately after the animals press the pedal and the injector is activated, otherwise the animal will not connect the sensations arising with their manipulations on the pedals.

In order to overcome this part of the technical difficulty and achieve the set goal, strychnine in the model was replaced by securinine, which is similar in pharmacological properties, whose convulsive effect, however, is not potentiated by opiates. The increase in excitation, which is an aversive factor, which, when using strychnine, is ensured by the potentiation of its convulsive effect by morphine, was simulated by an increase in the dose of securinin. For this, securinin was injected directly into the morphine infusion solution, so that the concentration of the drug in the solution remained the same as that which the animal was accustomed to during pre-narcotic anesthesia (otherwise the results before and after the aversion will not be comparable).

An infusion aversive mixture containing 0.4% morphine and 0.12% securinine, proposed to rats dependent on morphine, completely suppressed the self-administration reaction during the 4-hour experiment in all animals. The dose of securinin nitrate absorbed was 3-5 times lower than the convulsive threshold.

In contrast to the above analogues, the inhibition of the self-introduction reaction of the proposed method is stable. Not a single animal in which the self-administration reaction was inhibited was able to recover it upon returning to the infusion of pure morphine during regular sessions, as well as through special provocations, despite the fact that such attempts were made throughout the entire supply period, the duration of which reached in some cases 2 weeks.

It should be noted that this persistent suppression of the morphine self-introduction reaction is explained not by the extinction of the operant response of pressing the pedal in the delivery period, since the animal willingly carried it out at that time with food reinforcement, but by the extinction of the attraction specifically to morphine and all attempts to transfer the animals that passed the aversion of the securinine-morphine mixture from food reinforcement to morphine reinforcement was not successful.

The proposed method is implemented as follows.

An animal prepared according to the above procedure is placed in a Skin-5 nera cell daily for 4 hours, where it, when performing the operant reaction (press the pedal), receives reinforcement in the form of intravenous infusions of the drug infusion solution (the infusion solution is taken into account by diluting the official 1% solution of morphine hydrochloride with water for injection to a concentration of 0.4%).

Since the proposed method is aimed at suppressing the craving for opiates, i.e.

5 to overcome the state of mental dependence on the drug, then during the pre-preparation in the experiment it is necessary to obtain the equivalent of this clinical condition. Since the first three

0 days in the animal, residual manifestations of the instrumental food-producing reaction remain, and starting from 7-10 days recessive withdrawal symptoms (stitching, ptosis, piloereci) appear, indicating physical dependence, then the period from 4th to The 6th day of the experiment can be considered a model of the syndrome of mental dependence on opiates (Waldman A.V., Baba n E.A., Zvartau E.E.

0 Psychopharmacological and medical-legal aspects of substance abuse, - M., Medicine, 1988, p. 34). Therefore, experiments on the self-administration of morphine are repeated for five days, and on the sixth day with animals in

In which, by this time, the self-administration reaction of the drug is stable and sufficiently intense (at least 100 pedals for 4 hours), an aversion session is performed.

On this day, when preparing the infusion solution, the official 1% solution of morphine hydrochloride is not diluted with water for injection, but with the official 0.2% solution of securinine nitrate, so that the concentration of morphine in the infusion solution

5 was still 0.4% (with the concentration of securinin in the mixture becoming 0.12%). The injector is charged with this mixture and the animal is again placed in the chamber. The effectiveness of suppressing drug addiction is judged by the change in the number of pedal presses during a session.

The next day, to check the strength of the resulting aversion, the animal was again transferred to a 0.4% morphine solution without

5 securinin. When it is revealed that morphine no longer supports the self-administration reaction, they return to the nutritional support of the operant reaction to determine whether inhibition of the self-administration reaction is a consequence of the extinction

operant reaction in general. Over the next period, provocative (provocative, food supplementation with simultaneous self-administration of morphine) or narcotic (forced administration of 5-10-20 mg / kg of morphine prior to the start of self-administration) are carried out.

Example 1. Protocol No. 31 of 8.12.89

-22.12.89.

The rat is male, not purebred, weight 210 g, No. 14.

Cannula was implanted on 8.12.89.

The experiment diary is given in table 1.

Thus, a rapid increase in the dose of the drug absorbed during the session was observed during the period of anesthesia (moreover, on the 4th and% 4th day of the experiment in a well-fed animal, which indicates an attraction specifically to morphine); a critical decrease in the absorbed dose during an aversion session with the securinin-morphine mixture (day 6); and the lack of recovery of the self-administration reaction of morphine in the equitive period while maintaining operant skills.

PRI me R 2. Protocol No. 56 dated 12.12.90

-03.01.91.

The rat is male, not purebred, weight 190 g, No. 39.

Cannula was implanted on 12.12.90.

The experiment diary is given in table 2.

A steady, although not so steep, as in Example 1, an increase in the absorbed dose during anesthesia was noted; a critical decrease in absorbed dose during an aversion with a securinin-morphine mixture (6th day); and the lack of recovery of the self-administration reaction in the delivery period, despite seven-fold food provocations.

Example 3. Protocol No. 58 of 01.19.91

02.02.91.

The rat is male, not purebred, weight 220 g, No. 41.

The cannula was implanted on 01.19.91.

The diary of the experiment is given in table.Z.

A steady increase in the dose absorbed during the session during anesthesia and a critical decrease during the aversion of the securinin-morphine mixture were noted. In the delivery period, the preliminary forced administration of morphine to the animal restored the drug's self-administration, but only for the duration of the session immediately following such a provocation. Spontaneous (non-provocative) self-administration reaction during

subsequent sessions remained extinct. The observed effect of the pre-administration of morphine, the revitalization of the self-introduction reaction is likely associated with the neurotoxic effect of morphine, one of the manifestations of which is the stereotypical gnawing of the pedal, which leads to the actuation of the injector and stimulates

0 true spontaneous self-introduction. It is worth noting that the stereotypical phase is also presented in the usual morphine self-introduction session. It occurs at the 2nd - 3rd hour of the experiment, when at the initial stage

In experiment 5, due to controlled animal self-administration, a sufficient dose was obtained to exhibit neurotoxic effects.

According to the proposed methodology carried out

0 10 animals, which turned out to be sufficient to obtain reliable results for all studied parameters (correlation between stereotypes of anesthesia in different animals, differences in stress

5 self-administration reactions at all stages of the experiment: narcotization-aversi - postversion and others). In all cases, p is 0.05.

The data obtained indicate that the proposed method of aversion has a fundamentally new mechanism of action with respect to existing ones. Its effect is not a self-administration reaction of morphine is uniquely inhibitory, unlike alpha-blockers, but at the same time,

5, it does not prevent the appearance of the main signs of opium intoxication, as opiate receptor blockers do. It remains to be assumed that the described method modifies opium addiction,

0 making it subjectively unpleasant for the animal so much that it subsequently refuses even pure morphine without securinine, only by tasting it.

Thus, the suppression of attraction to

5 morphine in dependent animals by the proposed method is much more effective than its analogues + predecessors because it leads to the inhibition of the self-introduction reaction, which is irreversible in the framework of the experiment.

Claims (1)

SUMMARY OF THE INVENTION A method for treating opiate dependence in an experiment by preparing an animal using an intravenous self-administration of a preparation, characterized in that, in order to increase the effectiveness of treatment by obtaining an irreversible aversion, a morphine-securinine mixture containing 0.4% is administered drug and not less than 0.1% analeptic. Table 1 + - CB - self-introduction. table 2 Notes: - Food provocation. An animal that has passed the aversion of securinin - with a morphine mixture in a state of light food deprivation, half an hour of self-administration of morphine is fed on pedals; - the appearance of signs of withdrawal symptoms (pilo erection, spitting). Continuation of table 2 Table 3