Department of Pharmacology (D.R.M., L.R.G., J.H.W., C.P.F.), Department of Psychiatry (C.P.F.), and Addiction Research, Treatment & Training Center of Excellence (D.R.M., L.R.G., J.H.W., C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (S.M.H., A.D.).
Department of Pharmacology (D.R.M., L.R.G., J.H.W., C.P.F.), Department of Psychiatry (C.P.F.), and Addiction Research, Treatment & Training Center of Excellence (D.R.M., L.R.G., J.H.W., C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (S.M.H., A.D.)
J Pharmacol Exp Ther. 2019 Jan;368(1):88-99. doi: 10.1124/jpet.118.252353. Epub 2018 Nov 6.
Opioid abuse remains a serious public health challenge, despite the availability of medications that are effective in some patients (naltrexone, buprenorphine, and methadone). This study explored the potential of a pseudoirreversible mu-opioid receptor antagonist [methocinnamox (MCAM)] as a treatment for opioid abuse by examining its capacity to attenuate the reinforcing effects of mu-opioid receptor agonists in rhesus monkeys. In one experiment, monkeys responded for heroin ( = 5) or cocaine ( = 4) under a fixed-ratio schedule. Another group ( = 3) worked under a choice procedure with one alternative delivering food and the other alternative delivering the mu-opioid receptor agonist remifentanil. A third group ( = 4) responded for food and physiologic parameters were measured via telemetry. The effects of MCAM were determined in all experiments and, in some cases, were compared with those of naltrexone. When given immediately before sessions, naltrexone dose-dependently decreased responding for heroin and decreased choice of remifentanil while increasing choice of food, with responding returning to baseline levels 1 day after naltrexone injection. MCAM also decreased responding for heroin and decreased choice of remifentanil while increasing choice of food; however, opioid-maintained responding remained decreased for several days after treatment. Doses of MCAM that significantly decreased opioid-maintained responding did not decrease responding for cocaine or food. MCAM did not impact heart rate, blood pressure, body temperature, or activity at doses that decreased opioid self-administration. Because MCAM selectively attenuates opioid self-administration for prolonged periods, this novel drug could be a safe and effective alternative to currently available treatments for opioid abuse.
尽管有一些有效的药物（纳曲酮、丁丙诺啡和美沙酮），阿片类药物滥用仍然是一个严重的公共卫生挑战。本研究通过考察其作为治疗阿片类药物滥用的潜在能力，探索了一种假不可逆的μ-阿片受体拮抗剂[甲氧基肉桂酰胺（MCAM）]的可能性，该药物通过减弱μ-阿片受体激动剂在恒河猴中的强化作用来治疗阿片类药物滥用。在一项实验中，猴子通过固定比例程序响应海洛因（=5）或可卡因（=4）。另一组（=3）通过选择程序工作，其中一个替代方案提供食物，另一个替代方案提供μ-阿片受体激动剂瑞芬太尼。第三组（=4）通过遥测法响应食物，测量生理参数。在所有实验中确定了 MCAM 的作用，在某些情况下，将其与纳曲酮进行了比较。纳曲酮在治疗前立即给予，剂量依赖性地降低了海洛因的反应，降低了瑞芬太尼的选择，同时增加了食物的选择，纳曲酮注射后 1 天反应恢复到基线水平。MCAM 还降低了海洛因的反应，降低了瑞芬太尼的选择，同时增加了食物的选择；然而，阿片类药物维持的反应在治疗后几天仍持续下降。显著降低阿片类药物维持反应的 MCAM 剂量不会降低可卡因或食物的反应。MCAM 在降低阿片类药物自我给药的剂量下，不会影响心率、血压、体温或活动。由于 MCAM 选择性地延长时间减弱阿片类药物的自我给药，这种新型药物可能是目前阿片类药物滥用治疗的一种安全有效的替代方法。
