urb-597 and Morphine-Dependence

Inhibitors of the endocannabinoid metabolic enzyme fatty acid amide hydrolase exert therapeutic effects, but might also be associated with some of the adverse effects of cannabis. However, at least one fatty acid amide hydrolase inhibitor, URB597, has beneficial effects without signs of abuse or dependence. Although previous investigations have evaluated URB597-morphine interactions, the effects of URB597 on morphine tolerance and cognition deficits have not been studied previously. Rats were rendered tolerant to or dependent on morphine by an injection of morphine (10 mg/kg, subcutaneous) twice daily, respectively, for 7 or 10 days. URB597 (1 mg/kg, intraperitoneal) was administered before morphine. The tail-flick and passive avoidance learning tests were used to evaluate tolerance and cognition. Chronic morphine injection led to significant tolerance to the antinociceptive effect on days 5 and 7. URB597 completely prevented the development of morphine tolerance. URB597 also enhanced memory acquisition in the passive avoidance learning test, and although morphine impaired memory, URB597 alleviated this effect. These data show that URB597 protects against tolerance and memory deficits in chronic usage of morphine and suggests URB597 as a promising candidate for the treatment of adverse effects of opioids.

Topics: Amidohydrolases; Analgesics, Opioid; Animals; Avoidance Learning; Benzamides; Carbamates; Cognition Disorders; Drug Tolerance; Enzyme Inhibitors; Male; Memory Disorders; Morphine; Morphine Dependence; Nociception; Psychotropic Drugs; Random Allocation; Rats, Wistar

Chronic morphine exposure causes tolerance and dependence. The cessation of morphine consumption induces a withdrawal syndrome that may involve cannabinoids and is characterized by undesirable psychological and physical signs. The present study examined whether augmentation of the endocannabinoid system by inhibition of fatty acid amide hydrolase could suppress the morphine withdrawal syndrome in morphine-addicted rats. Morphine dependency was induced by 7 consecutive days of morphine injection. The morphine-addicted rats received URB597 (1, 0.5, 0.3, 0.1, 0.03 mg/kg), a fatty acid amide hydrolase inhibitor, before the precipitation of morphine withdrawal syndromes by naloxone. Withdrawal symptoms including jumping, teeth chattering, paw tremor, wet dog shakes, face grooming, penis licking, standing, rearing, sniffing and percent of weight loss were recorded during 30 min after naloxone injection. The results showed that the morphine withdrawal precipitated rats had significantly more withdrawal symptoms than naive control rats and the administration of URB597 (all doses except 0.03 mg/kg) reduced most of the morphine withdrawal symptoms. We conclude that the administration of URB597 modulated morphine withdrawal symptoms. This finding shows that endocannabinoids interact with the opioid system during the morphine withdrawal period and that potentiation of the endogenous cannabinoid system by URB597 may be a new target strategy for the management of morphine addiction.

Topics: Amidohydrolases; Animals; Behavior, Animal; Benzamides; Cannabinoid Receptor Modulators; Carbamates; Humans; Male; Morphine Dependence; Random Allocation; Rats; Rats, Wistar; Substance Withdrawal Syndrome

Converging evidence suggests that the endogenous cannabinoid (eCB) system is involved in extinction of learned behaviours. Using operant and classical conditioning procedures, the potential of the fatty acid amide (FAAH) inhibitor, URB-597, and the CB(1) antagonist/inverse agonist, SR141716, to promote and inhibit (respectively) extinction of learned responses previously motivated by either rewarding or aversive stimuli was investigated. In the operant conditioning procedure (Expt. 1), rats previously trained to lever press for sucrose reward were administered URB-597 (0.3 mg/kg) or the CB(1) antagonist/inverse agonist SR141716 (2.5 mg/kg) prior to each of three extinction trials. In the conditioned floor preference procedure (Expts 2a-d), rats trained to associate morphine with one of two distinctive floors were administered one of several doses of the CB(1) antagonist/inverse agonist, AM-251 (Expt 2a) or URB-597 (Expt 2b and 2d) prior to each extinction/test trial wherein a choice of both floors was presented and prior to forced exposure to each floor (Expt 2c). In the conditioned floor aversion procedure (Expt. 3), rats trained to associate a naloxone-precipitated morphine withdrawal with a floor cue were administered URB-597 or SR141716 prior to each of 24 extinction/testing trials. URB-597 did not promote and SR141716 did not reduce extinction rates for sucrose reward-induced operant responding (Expt. 1) or morphine-induced conditioned floor preference (Expts. 2a-d). In contrast, URB-597 facilitated, whereas SR141716 impaired, extinction of the conditioned floor aversion (Expt. 3). These data support previous reports that the eCB system selectively facilitates extinction of aversive memories. URB-597 may prove useful in targeting extinction of aversively motivated behaviours.

Topics: Amidohydrolases; Animals; Benzamides; Cannabinoid Receptor Modulators; Carbamates; Choice Behavior; Conditioning, Psychological; Dietary Sucrose; Extinction, Psychological; Female; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Piperidines; Pyrazoles; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Reinforcement Schedule; Rimonabant; Species Specificity; Substance Withdrawal Syndrome