Krystal J H, Walker M W, Heninger G R
Abraham Ribicoff Research Facilities, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
Eur J Pharmacol. 1989 Feb 7;160(3):331-8. doi: 10.1016/0014-2999(89)90088-5.
Rhesus monkeys that received 15 daily injections of methadone (2 mg/kg i.m.) exhibited a characteristic opiate withdrawal syndrome after injection of naloxone (0.5 mg/kg i.m.) on the 16th day. In comparison, injection of naloxone (0.5 mg/kg i.m.) once every 2 days during a similar 15 day methadone treatment period in these same monkeys significantly attenuated the severity of the opiate withdrawal syndrome exhibited after naloxone injection on the 16th day. Each naloxone administration during the 15 day methadone treatment period elicited an opiate withdrawal syndrome that did not significantly differ on each of the 7 days it was given and was less severe than the syndrome precipitated by naloxone following 15 days of methadone without intermittent naloxone. The lack of increments in the withdrawal response to the seven naloxone injections during the 15 days of methadone treatment and the attenuation of the withdrawal response to naloxone on day 16 after intermittent naloxone administration during the 15 day methadone treatment period support the hypothesis that naloxone modifies opiate receptor mechanisms so that they revert to an agonist-naive state following antagonist exposure. These findings suggest that various agonist and antagonist opiate drug combinations or mixed agonist-antagonist drug could be clinically useful in the management of situations where physical dependence on opiates is a problem.
接受每日15次美沙酮注射（2毫克/千克，肌肉注射）的恒河猴，在第16天注射纳洛酮（0.5毫克/千克，肌肉注射）后出现了典型的阿片类戒断综合征。相比之下，在相同的15天美沙酮治疗期内，每隔2天给这些猴子注射一次纳洛酮（0.5毫克/千克，肌肉注射），显著减轻了第16天注射纳洛酮后出现的阿片类戒断综合征的严重程度。在15天美沙酮治疗期内每次注射纳洛酮都会引发阿片类戒断综合征，在给药的7天里，每次引发的症状没有显著差异，且比连续15天注射美沙酮而不间歇注射纳洛酮后由纳洛酮引发的综合征症状要轻。在15天美沙酮治疗期内，对7次纳洛酮注射的戒断反应没有增强，且在15天美沙酮治疗期内间歇注射纳洛酮后，第16天对纳洛酮的戒断反应减弱，这些结果支持了这样一种假说，即纳洛酮改变了阿片受体机制，使其在接触拮抗剂后恢复到未接触过激动剂的状态。这些发现表明，各种激动剂和拮抗剂阿片类药物组合或混合激动剂-拮抗剂药物在处理阿片类物质身体依赖问题的临床治疗中可能会有帮助。
