EP1814542A2 - Nouvelles compositions pharmaceutiques et leurs utilisations pour lutter contre les differentes formes d'accoutumance aux drogues - Google Patents

Nouvelles compositions pharmaceutiques et leurs utilisations pour lutter contre les differentes formes d'accoutumance aux drogues

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Publication number
EP1814542A2
EP1814542A2 EP05816959A EP05816959A EP1814542A2 EP 1814542 A2 EP1814542 A2 EP 1814542A2 EP 05816959 A EP05816959 A EP 05816959A EP 05816959 A EP05816959 A EP 05816959A EP 1814542 A2 EP1814542 A2 EP 1814542A2
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EP
European Patent Office
Prior art keywords
amisulpride
pharmaceutical compositions
dopaminergic
combination
compositions according
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EP05816959A
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German (de)
English (en)
French (fr)
Inventor
Mario Sanchez
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Trimaran Ltd
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Trimaran Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to the field of the necessities of life and, more particularly, the field of therapeutics.
  • compositions intended to help the return to abstinence in a powerful way, the habitués of the drugs causing habituation and, thus, to get them to find a social and / or professional activity normal.
  • Addiction or addiction
  • Addiction can be defined as a behavioral disorder, characterized by a compulsive search for the product that causes this dependence, despite the adverse consequences for health, family life, work, etc., of which it is perfectly conscious the dependent person.
  • This dependence is due to the excessive and repeated stimulation of the opioid receptors, in particular of the mu type (Matthes et al., Nature Nature, 1996,383,819-823), more particularly in the cerebral structures forming the limbic system (ventral tegmental area, nucleus accumbens , amygdala, prefrontal cortex, etc.). It gradually follows changes in the functioning of the neurons that maintain this state of dependence and, above all, cause a very powerful and very long-lasting remanence of the effects of the substance.
  • the ideal would be to find a treatment that significantly facilitates access to abstinence.
  • the neurotransmitter involved in the euphoric effects of opioids is dopamine, released by dopaminergic terminations, especially in the nucleus accumbens and prefrontal cortex. Dopamine interacts with the D1, D2 and D3 receptors, essentially to lead to the hedonic effect.
  • neuroleptics The blocking of these receptors by neuroleptics is widely used in certain major disorders, such as schizophrenia, panic attacks or generalized anxiety. This type of treatment generally leads, in the patient, to a dysphoric state with reduced hedonic effects and social activities.
  • the invention which is the subject of the present patent application, lies in the fact that, against all odds, the treatment of persons dependent on heroin and opioids, but also, to a lesser extent, on psycho-stimulants (cocaine by example), by a dopamine receptor antagonist, in particular of the D2 and / or D3 type, leads to a rapid improvement of the state of internal tension leading to the compulsive search of the addictive substance.
  • the combination when administering the two substances (a dopaminergic antagonist and a prodopaminergic product) is capable of producing an anti-addiction effect, at least during the first weeks of treatment.
  • the improvement of the physical state of the dependent persons is such as to allow to establish very quickly a research of the root causes of the compulsive behavior, characteristic of the addiction.
  • the invention therefore specifically relates to a pharmaceutical composition containing a combination of two drugs, preferably in the form of a kit, intended to be administered, simultaneously or successively, to facilitate weaning, which consists of a combination of a partial antagonist or dopamine receptors, in particular D2 and D3 receptors, and a pro-dopaminergic product, preferably an opioid-substitution product, in the form of a pharmaceutical composition for parenteral or transdermal oral administration. .
  • the dopaminergic antagonist is preferably a D2 antagonist, or especially a D2 / D3 antagonist.
  • Dopaminergic antagonists include pure dopaminergic antagonists and partial dopaminergic antagonists, further manifesting a serotoninergic component.
  • dopaminergic antagonists the most used molecules are:
  • dopamine antagonist substances such as sulpiride, metoclopramide, or alternatively olanzapine or alphaalperidol may also be used.
  • the prodopaminergic product may be defined as a substance capable of binding to or in opioid receptors, which exhibits only weakly euphoric activity and / or which exhibits only a limited addictive effect.
  • methadone, buprenorphine, the product called LAM, nalorphine, naltrexate, Levallorphan, and, in a general way, any substance described as possessing such property, may be mentioned.
  • the invention therefore lies in the fact of administering such an association either simultaneously in the form of a composition single pharmaceutical defined, either in the form of a kit containing each of said active ingredients in a separate form which can thus be administered at variable dosages, or at different rates or in a different order, or in different forms.
  • the concentrations of active ingredients may also vary, from a strong dosage to a lower dosage, depending on the therapeutic needs, the continuation of treatment and the occurrence of side effects.
  • Amisulpride is one of many representatives of the benzamide series disclosed in US Patent 4,401,822 as an anti-apomorphine substance.
  • the synthesis of amisulpride in racemic or enantiomerically pure form [S (-)] is described in application PCT / EP99 / 05325, as well as that of its salts.
  • Amisulpride is described in pharmacology as displacing [ 3 H] racloprid of limbic D2 receptors. Amisulpride is also antagonistic against apomorphine. Amisulpride, because of its central action, may be considered an antipsychotic drug in subjects with schizophrenia, especially with fewer side effects than known antipsychotic neuroleptic drugs, such as extrapyramidal syndrome, etc. . Amisulpride is therefore a known medicine, hitherto used in other neuro-psychiatric indications.
  • the anti-addictive effect sought in the present invention is another antagonistic effect vis-à-vis the dopaminergic receptors, including D2 and D3 receptors.
  • the doses administered in the context of the pharmaceutical compositions according to the invention will vary according to the desired effect, the age of the addictive drug addiction and the intensity of the action against the desired addiction.
  • the doses of anti-dopaminergic substance may vary from 1 mg to 1200 mg per unit dose. Doses of prodopaminergic substances, amounting to a plateau, will range from 0.2 mg to 300 mg;
  • the combination will be formed of tablets of anti-dopaminergic substance, such as amisulpride, containing from 400 mg to 1200 mg of active ingredient and tablets of prodopaminergic substance, such as buprenorphine, at a dose of 0, 2mg to 30 'mg per unit dosage.
  • the doses of prodopaminergic substance will be higher in the rapid metabolisers which thus support higher doses (200 to 300 mg).
  • kits containing for example two vials of a solid or liquid preparation, one of the vials containing a solution of anti-dopaminergic substance, the other vial containing a solution or suspension of substitute substance, such as syrup or an aqueous suspension of methadone.
  • Injectable forms can also be made. They allow the simultaneous administration of the two active ingredients of the combination. They are justified in particular for the realization of long-acting deposit forms. Transdermal forms may also be contemplated with a prolonged effect.
  • the usual dosing regimen usually involves using low doses of the prodopaminergic drug and then gradually increasing the doses to achieve a "plateau" effect.
  • the daily dosage will range from 400 to 1200 mg, and from 100 to 400 mg.
  • the dosage will range from 1 to 16 mg per day.
  • prodopaminergic products including methadone
  • the doses of buprenorphine, morphine sulphate or nalorphine will be of the same order of magnitude.
  • the order of administration of the two components of the combination according to the invention is not critical and can be modulated according to the needs of the therapy. It seems preferable to first administer the pro-dopaminergic substance and then the anti-dopaminergic product. It is possible, on the contrary, to administer in the first place the anti-dopaminergic product then followed by the administration of the pro-dopaminergic product. In any case, it is more convenient that the administration of the two active ingredients is simultaneous.
  • the invention also relates to a pharmaceutical composition consisting of a combination of an anti ⁇ dopaminergic product or a salt thereof, and buprenorphine containing, for example, 400 to 1200 mg of amisulpride and 0.2 to 30 mg of buprenorphine in an excipient or an inert, non-toxic, pharmaceutically acceptable vehicle, by modulating the dosage, first crescent and then when the threshold effect is reached, the dosage is decreased.
  • Another object of the invention resides in the production of a kit containing a first pharmaceutically appropriate dosage of anti-dopaminergic substance in base form or in salt form, in racemic form or in enantiomeric form, at the dose of 100 to 400 mg and a second pharmaceutically appropriate dosage of methadone containing 5 to 60 mg methadone per unit dose.
  • the invention also relates to an anti-addiction drug consisting of the combination of sulpiride in racemic or optically active form, free or salified with a mineral or organic acid, and buprenorphine.
  • the combination according to the invention is intended to be administered one to four times a day, at predetermined intervals, to ensure constant impregnation of the subject drug.
  • the pharmacological and clinical tests show the effectiveness of the combination according to the invention.
  • the invention also relates to a method for combating the various forms of addiction to licit or illicit drugs by administering to subjects who are addicted to illicit drugs a sufficient and effective amount of a combination of a prodopaminergic agonist. and a dopamine antagonist simultaneously, in a single dosage form or separately, or batchwise, by first administering the dopaminergic agonist, in a pharmaceutical form • determined, then the dopaminergic antagonist in another dosage form, example in kit form.
  • the method described above is particularly suitable for combating addiction to opiate drugs, such as heroin. It is also used in the fight against the use or abuse of active ingredients that lead to addiction, such as, for example, amphetamine and its derivatives, alcohol, cocaine, and NDMA.
  • opioid receptors make it possible to obtain a large number of physiological and pharmacological responses. Indeed, the opioid system is involved in the modulation of stress, pain, mood, cardiovascular function, and food intake (Vaccarino et al., 2000).
  • These receptors have a sequence homology of 60% in humans, the most conserved sequences being the transmembrane domains and the intracellular loops. In addition, they are distributed differently in the central nervous system. ⁇ opioid receptors are widely present throughout the central nervous system, with very high concentrations in certain regions such as basal ganglia, limbic structures, thalamic nuclei, and regions important for nociception. The delta and kappa receptors have a smaller distribution, they are mainly present in the ventral and dorsal striatum for the first, and the dorsal striatum and the preoptic area for the second (Mansour et al., 1988).
  • opioid receptors have been extensively studied in different tissues, cell types or neuron preparations. These three receptors have been shown to be coupled to Gi / Go proteins that modulate many effectors. Indeed, opioid receptors inhibit adenylate cyclase activity (Sharma et al. al., 1977), resulting in decreased intracellular cAMP levels, decreased calcium conductance (Hescheler et al., 1987, Surprenant et al, 1990), stimulated potassium channels (North et al. intracellular calcium levels (Jin et al., 1992). More recently, it has been shown that these receptors are capable of generating mitogenic signals by activating the MAP kinase pathway (Fukada et al., 1996).
  • the endogenous ligands of the opioid receptors are the endomorphins (Hughes et al, 1975). They are neuropeptides released into the synaptic space, from large dense-heart vesicles, as a result of stimulation of neurons where they coexist with other neurotransmitters. Endomorphins derive from distinct precursors and are heterogeneously present in the different neuronal populations of the central nervous system.
  • Proopiomelanocortin (or POMC) gives rise to ⁇ -endorphin and related peptides
  • pro-enkephalin A is responsible for the enkephalins (Met- and Leu-enkephalin) and related peptides
  • prodynorphin gives rise to neo- endorphins and dynorphin (Akil et al., 1998).
  • Enkephalins have a very short lifespan after their release (less than a minute). This brevity is not due, as for most classical neuromediators, to a recapture system but to their enzymatic degradation. Met-enkephalin (Try-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) are rapidly hydrolysed by cleavage of the Gly-Phe bond by a peptidase initially called enkephalinase, which has since been shown to be identical to neutral endopeptidase (NEP), and at the level of the Tyr-GIy bond by aminopeptidase N (APN) (Roques, 1986). These two enzymes belong to the same group of zinc metallopeptidases.
  • Inhibitors of enkephalin catabolism increase the extracellular concentration of enkephalins without affecting their release (Daugé et al., 1996, Bourgoin et al., 1986, Waksman et al., 1985).
  • the advantage of these molecules is that, even at very high doses, they never induce pharmacological responses as powerful as morphine (Ruiz-Gayo et al., 1992, Abbadie et al., 1994), and are therefore lacking the classic side effects of opioids (constipation, dry mouth, itching, irregular periods, and at a more serious level, gastrointestinal disorders and respiratory depression).
  • the oldest known opioid receptor ligand used in medicine is morphine, an alkaloid derived from the Indian poppy.
  • Heroin diacetylmorphine, diamorphine
  • diamorphine diamorphine
  • this substance is very popular with drug addicts, because of its rapid penetration into the brain where it generates an answer called orgasmic, the "high”.
  • opioid agonists are now used in substitution treatments, such as methadone and buprenorphine.
  • Methadone is a synthetic opioid and, like morphine, is a preferred ⁇ receptor agonist.
  • DAMGO and DPDPE are conventionally used as selective ligands, respectively ⁇ and ⁇ receptors in experimental pharmacology. (Handa et al, 1981, Mosberg et al, 1983).
  • opioid antagonists Another class of exogenous ligands for opioid receptors exists: opioid antagonists.
  • naloxone is used therapeutically in the treatment of acute opioid poisoning. This molecule binds with the same affinity to both ⁇ and ⁇ receptors.
  • Another known antagonist is naltrindole, it binds with a very high affinity for ⁇ receptors (Fang et al, 1994) .It is widely used in experimental pharmacology.
  • addiction / addiction is a syndrome in which the consumption of a product becomes a higher requirement than other behaviors previously of maximum importance.
  • Addiction sets in with the repetition of drug taking and is characterized by a compelling need for the drug that leads to its compulsive search.
  • Dependence has two facets: physical and psychic.
  • the physical component requires the addict to consume drugs or pain specific to the withdrawal syndrome (which, except exceptional case, is not fatal despite the strength of pain). It may disappear after a few days.
  • the psychic component is the desire of the addict to start again, it is associated with a strong stimulation of the brain by the reinforcement / reward system and is the cause of many relapses in drug addiction. It can last several years.
  • Tolerance is the process of adapting an organism to a substance, which results in the progressive weakening of its effects, and leads to the need to increase the dose to achieve the same effects. In animals, tolerance leads to a decrease in the behavioral effects induced by the drug following repeated administration.
  • Opioid withdrawal is manifested inter alia by hypertension and abdominal cramps, but also by anhedonia and dysphoria.
  • opioid withdrawal may be caused by the administration of an opioid antagonist, naloxone.
  • opioid antagonist naloxone
  • Several behavioral changes are then observed in morphine-dependent rats: increased grooming, chewing, blinking, but also diarrhea or weight loss.
  • D1-like receptors D1 and D5 are coupled via Gs to adenylate cyclase and allow the production of cAMP that triggers many protein kinase A dependent metabolic responses.
  • D2-like receptors D2, D3 and D4 are coupled to Gi / o and inhibit the synthesis of cAMP, which facilitates in particular the opening of hyperpolarizing K + channels.
  • Dopamine neurons are mainly assembled in two mesencephalic nuclei.
  • One is the tegmentum or ventral tegmental area (ATV, or mesencephalic area AlO) whose axonal projections innervate the cortex (especially in its anterior part), the limbic system (especially the septum and amygdala) and nuclei of the base (putamen and nucleus accumbens).
  • ATV tegmentum or ventral tegmental area
  • AlO mesencephalic area
  • Most of these fibers pass through the medial telencephalic beam (FMT) and are involved in the processing of cognitive-affective information.
  • FMT medial telencephalic beam
  • this neural wiring belongs to the reward / reinforcement system that produces a very strong brain stimulation in order to experience pleasure (hedonic action) in behaviors essential to the survival of the species or the individual. It is this motivational circuit that is hijacked by drugs. Thus, these, by producing pleasure, motivate the individual towards compulsive behavior where drug use replaces survival behaviors.
  • the other dopaminergic nucleus is the substantia nigra (substantia nigra or substantia nigra or mesencephalic area A9) that emits axons to the striatum (caudate nucleus and putamen) and participates in the control of locomotion. Drugs that alter the level of dopamine release in the striatum disrupt motor skills.
  • Morphine administration stimulates the activity of dopaminergic neurons in the substantia nigra and ATV, resulting in increased dopamine release in the caudate-putamen nucleus and the nucleus accumbens (Matthews and German, 1984; Spanagel et al., 1990, Di Chiara and North, 1992).
  • Amisulpride is a molecule chemically related to benzamides. At low doses, amisulpride has an antagonistic effect on the D2 and D3 presynaptic receptors (net effect: facilitation) of the frontal cortex. In contrast, amisulpride used at high doses inhibits the postsynaptic D2 and D3 receptors (net effect: blocking) in the limbic system. It is also devoid of extra-pyramidal effects, since having only weak activity in the striatum (Perrault et al., 1996). All these elements make this molecule an atypical anti ⁇ psychotic, today used in the treatment of positive and negative symptoms of schizophrenia. MATERIALS AND METHODS
  • mice Male OFl mice weighing about 20 g at the beginning of the experiments (Charles River, France). They live in an environment whose daily light cycle (7h30, 19h30) is constant throughout the year, and the temperature is maintained at around 22 0 C. The mice have free access to water and water. food, and the experiments are carried out in accordance with the international rules of ethics of animal experimentation.
  • the animals are chronically treated intraperitoneally (IP) with amisulpride or saline. Injections are carried out twice a day, with an interval of about eight hours between each administration, over a period ranging from five days to three weeks. On the day of the pharmacological test, the animals do not receive amisulpride.
  • the RJB101 is administered on the day of the intravenous (IV) test, 10 minutes before the start of the test (except for measurements of locomotor activity carried out immediately after the injection).
  • Amisulpride (solution for injection 200 mg / 4mL) is used in diluted form with saline.
  • RB101 is a synthetic product described by Baamonde et al. Europ J Pharmacol (1992) T
  • Methadone hydrochloride and morphine hydrochloride are commercial products. They are dissolved in physiological saline.
  • mice are placed individually in a plastic cage (255 cm x 205 cm) isolated from the noise and are exposed to a light intensity of 5 lux. The movements of the animals are captured by photocells for 45 minutes and recorded by a computer. The animals receive the vehicle (ethanol (10%) / Cremophor EL (10%) / water (80%)) or RB101 (5 mg / kg) intravenously at a volume of 0.1 ml / 10 g. . The experiment begins immediately after the injection of the product. In this study, the term "locomotor activity" only takes into account horizontal movements of animals.
  • mice are placed individually inside a cylinder, on a plate heated to 52 + 1 ° C. by a water circuit.
  • the latency time of the mouse jump is measured, the value 100 of the percentage of analgesia corresponding to a time limited to 240 seconds in order to avoid cutaneous lesions.
  • the test is performed 10 minutes after injection of RB101 (5 mg / kg, IV) or vehicle.
  • the results are expressed as a percentage of analgesia calculated by the following formula: (average of the latency times of the jump of the treated group - average latency times of the jump of the control group) / (240 - average latency times of the jump of the control group) x 100.
  • the results are expressed as mean ⁇ wk.
  • mice are placed individually in a cylindrical container filled with water at a height of 15 cm, the water being at room temperature. After a period of 2 minutes, the total time of immobilization of the animal is measured for 4 minutes. The movements necessary for the animal to keep the head out of the water are not counted.
  • the app ⁇ roil preferably plaep. packaged consists of a box divided into three separate compartments: a black compartment with a smooth floor, a black and white striped compartment with a rough floor, and a neutral central compartment.
  • the test is conducted in 3 phases: - a pre-test phase: the animal is placed in the neutral central compartment and has free access to the three compartments of the device for 20 minutes.
  • the time spent inside each compartment is recorded using a camera connected to a computer. Mice exhibiting a spontaneous preference for one of the compartments (that is, passing more than 75% of the time allocated in one of the side compartments) are excluded from the experiment.
  • the animals are randomized to give them treatment (morphine or saline, SC) and the compartment in which they will receive the drug (black or black and white striped compartment).
  • SC morphine or saline
  • a conditioning phase the animals alternately receive morphine (10 mg / kg, SC) or physiological saline for three consecutive days, the physiological saline being injected in the morning and the morphine in the afternoon for the same animal. Animals are kept in either compartment for about 20 minutes immediately after injection. The compartment associated with the drug is always the same for the same mouse.
  • test phase as for the pre-test phase, the animals are placed in the central compartment and have free access to the three compartments. They receive no injection of morphine or saline that day.
  • the scores correspond to the difference between the time spent during the test phase and the pretest phase in the compartment associated with morphine.
  • ANOVA One-way analysis of variance
  • the hot plate test is conventionally used to evaluate the analgesic power of molecules. It is a method that involves a response to a central integration, the jump being associated with a desire to escape the painful stimulus.
  • the analgesic potency of RB101 in this test was previously shown (Noble et al, 1992), and a dose-effect was demonstrated to start this study. In fact, we seek the dose of RB101 for which we obtain about 40% of analgesia, which allows to possibly observe a potentiation of the effects thereof by amisulpride. Three doses were tested: 2.5 mg / kg, 5 mg / kg and 10 mg / kg, intravenously, 10 minutes before the start of the test.
  • the dose of 5 mg / kg allows analgesia of AS, 2% ⁇ 10.6%. This is the dose chosen for combination with ramisulpride.
  • a molecule with a dopaminergic antagonist activity decreases locomotor activity. It is this property that is involved in determining the dose at which amisulpride has a dopaminergic antagonist activity in mice (an effect on D2 and D3 postsynaptic receptors, and not on D2 auto-receptors and D3).
  • the doses are: 0.5mg / kg, 2mg / kg, 10mg / kg, 20mg / kg and 50mg / kg.
  • the decrease in locomotor activity is significant from 10 mg / kg.
  • the chosen dose is 20 mg / kg, a dose for which dopamine antagonist activity is evident and possible discussion. 2. Determination of duration of treatment with amisulpride (amisulpride / RB101 combination and measurement of locomotor activity)
  • RB101 In contrast to araisulpride, RB101 alone causes an increase in locomotor activity in mice (Baamonde et al., 1992).
  • the treatment with amisulpride (20 mg / kg, IP, 2 times / day) was first performed for 3 weeks after which RB101 (5mg / kg, IV) was injected and the measured locomotor activity immediately after, for 45 minutes.
  • the potentiation of the effects of RB101 by amisulpride persists even after only five days of treatment.
  • the locomotor activity is therefore measured after three days or ten days of treatment interruption, in mice treated five days according to the figure below:
  • the forced swimming test is conventionally used to evaluate the antidepressant effect of molecules.
  • RB101 alone is endowed with antidepressant-like properties (Baamonde et al., 1992), since it reduces the duration of immobility of the mice in this test.
  • the treatment with amisulpride is carried out for five days, and the RB101 is injected on the day of the test (the day after the cessation of treatment).
  • the treatment with amisulpride is carried out for five days, and the RB101 (5 mg / kg, IV) is injected on the day of the test (the day after the cessation of the treatment).
  • RB101 has an analgesic effect by itself (38.4% ⁇ 10.8%).
  • the amisulpride / RB101 combination is at a level of analgesia of 49.6% ⁇ 8.9%.
  • the animals are packaged as described in the "Materials and Methods" chapter.
  • the results obtained at the end of this conditioning are represented on the graph I placed in the appendix which shows the conditioned place preference.
  • mice of the two groups Morphine and Saline are then divided into two subgroups of equal size, one subgroup being treated with Amisulpride according to the usual protocol for five days, the other subgroup receiving serum injections. physiological.
  • a second test is carried out on these mice on the sixth day, the animals having been treated with Amisulpride receiving RB101 on the day of the test, the others receiving the vehicle.
  • Chart No. II The results of this test are shown in Chart No. II attached. It shows the effects of the treatment with amisulpride 20 mg / kg IP twice daily for 5 days associated with RB IM 55 mg / kg IV on the day of test 2) on animals used elsewhere in the test I.
  • mice of the Morphine group who have received this treatment seem, for their part, to be closer to the mice of the physiological serum group.
  • Chart III show the effect of treatment with Amisulpride (20 mg / kg ip twice daily for 5 days) + RB 101 (5 mg / kg IV, on test day 2), 4 days after test 2, on the same animals p ⁇ 0.05 compared to the group morphine / Amisulprine + RBlM p ⁇ 0.05 compared to the control group
  • Amisulpride and Methadone Association Measurement of Locomotor Activity The treatment with Amisulpride is carried out for 5 days, and methadone is injected on the day of the test (0.25 mg / kg, IV). The methadone dose chosen causes a level of analgesia comparable to that of RB101 in the hot plate test.
  • the treatment with Amisulpride is carried out for 5 days, and methadone is injected on the day of the test (0.25 mg / kg, IV).
  • Chart V appended hereafter shows the measurement of the immobilization time in the forced swimming test after 5 days of treatment with Amisulpride (S20) at 20 mg / kg ip twice daily.
  • Graph VI shows the measurement of locomotor activity after 5 days of treatment with Amisulpride (S24) at a dose of 20 mg / kg ip twice daily and 3 days after weaning.
  • Chart VII illustrates the results obtained after 10 days of weaning.
  • Graph VIII presents the results obtained by measuring the mobilization time in the forced swimming test in mice treated with Amisulpride ((S20) at a dose of 20 mg / kg ip twice day) for 5 days.
  • Graph IX shows the results obtained by measuring the immobilization time in the forced swimming test in mice treated with Amisulpride (S20) at a dose of 20 mg / kg ip twice daily during 5 days followed by 3 days of weaning.
  • the RB 101
  • methadone in place of RB101 did not provide portentiation of the effects of methadone when combined with chronic treatment with Amisulpride in locomotor and swimming tests forced.
  • the combination of RB101 and Amisulpride in the hot plate test showed no potentiation.
  • the combination amisulpride / RBlOl allows potentiation of the effects of RBlOl by acting preferentially at the level of opioid ⁇ receptors. It is also advantageous to use a preferential ⁇ -receptor antagonist, such as naltrindole, and to see if it is possible to block the effects obtained in the amisulpride / RB101 combination.
  • a preferential ⁇ -receptor antagonist such as naltrindole
  • methadone did not show a significant effect on locomotor activity and forced swimming, whereas at this same dose, it causes marked analgesia in the hot plate test.
  • methadone is known to have hyperlocomotor activity in mice (Browne, 1980), and has antidepressant effects as an opioid agonist. It should be verified that the lack of potentiation of the effects of methadone (0.25 mg / kg, IV) by Amisulpride obtained in this study is not due to the use of a low dose of methadone, renewing the tests carried out in a higher dose range (the risk then being to only touch ⁇ opioid receptors if too high doses are used).
  • Bontempi B Sharp FR. Systemic morphine-induced Fos protein in the rat striatum and nucleus accumfae ⁇ s is regulated by rau opioid receptors in the substantia nigra and ventral tegmental area.
  • Kieffer BL Befort K, Gaveriaux-Ruff C, Hirth CG.
  • the delta-opioid receptor isolation of a cDNA by expression cloning and pharmacological characterization.
  • Roques BP Fournie-Zaluski MC.
  • Enkephalin degrading enzyme inhibitors a physiological way to ⁇ ew analgesia and psychoactive agents.
  • Zinc metallopeptidases active site structure and design of selective and mixed inhibitors: new approaches in the search for analgesia and antihypertensives.
  • Valverde O Fournie-Zaluski MC, Roques BP, Maldonado R.
  • the CCKB antagonist PD-134,308 facilitates rewarding effects of endogenous enkephalins but does not induce preference in rats.

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