Morphine deprivation increases self-administration of the fast- and short-acting μ-opioid receptor agonist remifentanil in the rat
Morphine deprivation increases self-administration of the fast- and short-acting μ-opioid receptor agonist remifentanil in the rat
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DOI：
10.1124/jpet.108.139196
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发表时间：
2008-09-01
影响因子：
3.5
通讯作者：
Woods, James H.
中科院分区：
文献类型：
--
作者：
Cooper, Ziva D.;Truong, Yen Nhu-Thi;Woods, James H.
长期以来，人们一直假设阿片依赖和戒断会增强阿片的强化作用；然而，这些州的阿片激动剂自我给药情况还有待系统评估。为了解决这一问题，我们在吗啡依赖（MD）、吗啡依赖和戒断（MW）和非依赖对照(C)大鼠中评估了短效mu-阿片受体激动剂瑞芬太尼的强化特性。通过每天两次增加吗啡剂量，持续4天（10、20、30和40 mg/ kg s.c）建立依赖性，然后每天注射大剂量吗啡维持。吗啡剥夺引起的戒断（由体重减轻和痛觉过敏定义）在吗啡治疗后24小时明显，但在12小时不明显。瑞芬太尼自我给药0.4、0.8、1.6、3.2或6.4 μ g/kg/滴注)，在吗啡维持剂量后12或24小时连续20次，每日1小时疗程进行评估。与对照组相比，MD组表现出抑制瑞芬太尼自我给药，而MW组对每剂量的瑞芬太尼都表现出增强的反应。与对照组和MD组相比，MW组的反应增加导致瑞芬太尼剂量-反应曲线向上移动，这一效应仅在反复暴露于偶然性后才表现出来，表明吗啡戒断最终增强了瑞芬太尼的强化效应。
Opiate dependence and withdrawal have long been hypothesized to enhance the reinforcing effects of opiates; however, opiate agonist self-administration in these states has yet to be systematically assessed. To address this issue, the reinforcing property of the short-acting mu-opioid agonist, remifentanil, was assessed in morphine-dependent (MD), morphine-dependent and -withdrawn (MW), and nondependent, control (C) rats. Dependence was established by twice daily administration of increasing doses of morphine for 4 days (10, 20, 30, and 40 mg/ kg s. c.) and then maintained with a daily injection of the large dose. Morphine deprivation-induced withdrawal (defined by weight loss and hyperalgesia) was apparent 24, but not 12, h after morphine treatment. Remifentanil self-administration 0.4, 0.8, 1.6, 3.2, or 6.4 mu g/kg/infusion) was assessed over 20 successive, daily, 1-h sessions, either 12 or 24 h after the maintenance dose of morphine. Compared with the control group, the MD group demonstrated suppressed remifentanil self-administration, whereas the MW group exhibited enhanced responding for every dose of remifentanil. The increased responding observed in the MW group compared with the control and MD groups resulted in an upward shift in the remifentanil dose-response curve, an effect that was expressed only after repeated exposure to the contingency, demonstrating that morphine withdrawal ultimately enhances the reinforcing effects of remifentanil.