Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA.
Sci Transl Med. 2012 Aug 8;4(146):146ra110. doi: 10.1126/scitranslmed.3003948.
Buprenorphine, a synthetic opioid that acts at both μ and κ opioid receptors, can decrease cocaine use in individuals with opioid addiction. However, the potent agonist action of buprenorphine at μ opioid receptors raises its potential for creating opioid dependence in non-opioid-dependent cocaine abusers. Here, we tested the hypothesis that a combination of buprenorphine and naltrexone (a potent μ opioid antagonist with weaker δ and κ antagonist properties) could block compulsive cocaine self-administration without producing opioid dependence. The effects of buprenorphine and various doses of naltrexone on cocaine self-administration were assessed in rats that self-administered cocaine under conditions of either short access (noncompulsive cocaine seeking) or extended access (compulsive cocaine seeking). Buprenorphine alone reproducibly decreased cocaine self-administration. Although this buprenorphine-alone effect was blocked in a dose-dependent manner by naltrexone in both the short-access and the extended-access groups, the combination of the lowest dose of naltrexone with buprenorphine blocked cocaine self-administration in the extended-access group but not in the short-access group. Rats given this low dose of naltrexone with buprenorphine did not exhibit the physical opioid withdrawal syndrome seen in rats treated with buprenorphine alone, and naltrexone at this dose did not block κ agonist-induced analgesia. The results suggest that the combination of buprenorphine and naltrexone at an appropriate dosage decreases compulsive cocaine self-administration with minimal liability to produce opioid dependence and may be useful as a treatment for cocaine addiction.
丁丙诺啡是一种合成阿片类药物，可同时作用于 μ 和 κ 阿片受体，可减少阿片类药物成瘾者的可卡因使用量。然而，丁丙诺啡对 μ 阿片受体的强烈激动作用增加了其在非阿片类依赖可卡因滥用者中产生阿片类依赖的潜力。在这里，我们测试了以下假设：丁丙诺啡和纳曲酮（一种具有较弱的 δ 和 κ 拮抗剂特性的强效 μ 阿片受体拮抗剂）的组合可以阻断强迫性可卡因自我给药，而不会产生阿片类依赖。在进行短期（非强迫性可卡因寻求）或延长（强迫性可卡因寻求）可卡因自我给药的大鼠中，评估了丁丙诺啡和各种纳曲酮剂量对可卡因自我给药的影响。丁丙诺啡单独可重复降低可卡因自我给药。尽管纳曲酮在短接触和延长接触组中以剂量依赖性方式阻断了丁丙诺啡的这种单一作用，但最低剂量的纳曲酮与丁丙诺啡的组合阻断了延长接触组中的可卡因自我给药，但未阻断短接触组。给予这种低剂量纳曲酮和丁丙诺啡的大鼠没有表现出单独给予丁丙诺啡的大鼠中出现的身体阿片类戒断综合征，并且该剂量的纳曲酮不阻断 κ 激动剂诱导的镇痛。结果表明，丁丙诺啡和纳曲酮以适当剂量联合使用可减少强迫性可卡因自我给药，而产生阿片类依赖的风险最小，可能可作为可卡因成瘾的治疗方法。
