Mello N K, Lukas S E, Mendelson J H, Drieze J
Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, Belmont, Massachusetts 02178.
Neuropsychopharmacology. 1993 Nov;9(3):211-24. doi: 10.1038/npp.1993.57.
An opioid mixed agonist-antagonist analgesic, buprenorphine, significantly reduces cocaine self-administration by rhesus monkeys, but the relative contribution of buprenorphine's agonist and antagonist properties to this effect is unclear. This study examined the effects of concurrent treatment with naltrexone, a long-acting mu opioid antagonist, on buprenorphine's effects on cocaine and food self-administration by five rhesus monkeys. Cocaine (0.5 mg/kg per injection) and food self-administration (1 gm banana pellet) were maintained on a second order fixed ratio 4 (FR4) variable ratio (VR) 16:S schedule of reinforcement. Buprenorphine treatment alone (0.40 mg/kg/day) and in combination with ascending doses of naltrexone (0.05, 0.10, 0.20, and 0.40 mg/kg/day) was compared with naltrexone alone (0.40 mg/kg/day) and saline control treatment. Naltrexone was administered simultaneously or 20 minutes before buprenorphine administration. Each treatment condition was in effect for 10 days. Buprenorphine alone significantly reduced cocaine self-administration by an average of 53% in comparison to the saline treatment baseline (p < .01). When saline was substituted for buprenorphine, each monkey rapidly returned to its prebuprenorphine level of cocaine self-administration. Food self-administration in all conditions was equivalent to or significantly higher (p < .05) than food-maintained responding during the saline baseline. When buprenorphine and naltrexone were administered simultaneously, naltrexone significantly attenuated buprenorphine's suppressive effects on cocaine self-administration (p < .05 to .01). When naltrexone was administered 20 minutes before buprenorphine, there was a significant naltrexone dose-dependent (p < .01) decrease in buprenorphine's reduction of cocaine self-administration in comparison to the initial saline baseline. These data suggest that naltrexone antagonizes the partial mu agonist component of buprenorphine, which may be important for buprenorphine's effects on cocaine self-administration. Moreover, the addition of an opioid antagonist to reduce illicit diversion of buprenorphine might also compromise its effectiveness for treatment of dual dependence on cocaine and opiates.
阿片类混合激动剂-拮抗剂镇痛药丁丙诺啡可显著减少恒河猴的可卡因自我给药行为，但丁丙诺啡的激动剂和拮抗剂特性对该效应的相对贡献尚不清楚。本研究考察了长效μ阿片拮抗剂纳曲酮同时给药对丁丙诺啡对5只恒河猴可卡因和食物自我给药行为影响的作用。可卡因（每次注射0.5mg/kg）和食物自我给药（1g香蕉颗粒）维持在二级固定比率4（FR4）可变比率（VR）16:1的强化程序上。将单独使用丁丙诺啡治疗（0.40mg/kg/天）以及与递增剂量的纳曲酮（0.05、0.10、0.20和0.40mg/kg/天）联合使用的情况与单独使用纳曲酮（0.40mg/kg/天）和生理盐水对照治疗进行比较。纳曲酮在丁丙诺啡给药的同时或之前20分钟给药。每个治疗条件持续10天。与生理盐水治疗基线相比，单独使用丁丙诺啡可使可卡因自我给药平均显著减少53%（p<.01）。当用生理盐水替代丁丙诺啡时，每只猴子迅速恢复到丁丙诺啡治疗前的可卡因自我给药水平。在所有条件下，食物自我给药与生理盐水基线期间食物维持反应相当或显著更高（p<.05）。当丁丙诺啡和纳曲酮同时给药时，纳曲酮显著减弱丁丙诺啡对可卡因自我给药的抑制作用（p<.05至.01）。当纳曲酮在丁丙诺啡给药前20分钟给药时，与初始生理盐水基线相比，纳曲酮剂量依赖性地显著降低丁丙诺啡对可卡因自我给药的减少作用（p<.01）。这些数据表明，纳曲酮拮抗丁丙诺啡的部分μ激动剂成分，这可能对丁丙诺啡对可卡因自我给药的作用很重要。此外，添加阿片拮抗剂以减少丁丙诺啡的非法转移也可能损害其对可卡因和阿片类双重依赖的治疗效果。
