Reduction of opioid dependence by the CB(1) antagonist SR141716A in mice: evaluation of the interest in pharmacotherapy of opioid addiction.
Several compounds, mainly opioid agonists such as methadone, are currently used for long term medication of heroin addicts. Nevertheless, these maintenance treatments have the disadvantage to induce a dependence to another opiate. As interactions between opioid and cannabinoid systems have been demonstrated, the ability of the CB(1) antagonist, SR141716A to reduce morphine-induced addiction was investigated. The effects of SR141716A on the rewarding responses of morphine were evaluated in the place conditioning paradigm. No significant conditioned preference or aversion were observed after repeated treatment with the CB(1) antagonist alone. However, SR141716A was able to antagonize the acquisition of morphine-induced conditioned place preference. SR141716A was co-administered with morphine for 5 days, and the withdrawal syndrome was precipitated by naloxone administration. A reduction in the incidence of two main signs of abstinence: wet dog shakes and jumping was observed while the other were not significantly modified. In contrast, an acute injection of the CB(1) antagonist just before naloxone administration was unable to modify the incidence of the behavioural manifestations of the withdrawal, suggesting that only chronic blockade of CB(1) receptors is able to reduce morphine-induced physical dependence. Several biochemical mechanisms could explain the reduction of opioid dependence by CB(1) antagonists. Whatever the hypotheses, this study supports the reported interaction between the endogenous cannabinoid and opioid systems, and suggests that SR 141716A warrants further investigations for a possible use in opioid addiction.
Mas-Nieto
M
M
Département de Pharmacochimie Moléculaire et Structurale INSERM U266 - CNRS UMR8600, Université René Descartes, UFR des Sciences Pharmaceutiques et Biologiques, 4, Avenue de l'Observatoire, 75270 Paris Cedex 06, France.
Pommier
B
B
Tzavara
E T
ET
Caneparo
A
A
Da Nascimento
S
S
Le Fur
G
G
Roques
B P
BP
Noble
F
F
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects; D004399:Dynorphins / Q000378:metabolism; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009293:Opioid-Related Disorders / Q000188:drug therapy* / Q000523:psychology; D010880:Piperidines / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011863:Radioimmunoassay; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D000077285:Rimonabant; D013375:Substance Withdrawal Syndrome / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
D002186:Cannabinoids; D009292:Narcotic Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D017473:Receptors, Opioid, kappa; D009270:Naloxone; D004399:Dynorphins; D000077285:Rimonabant