Walker E A, Richardson T M, Young A M
Department of Psychology, Wayne State University, Detroit, MI 48202, USA.
Psychopharmacology (Berl). 1997 Sep;133(1):17-28. doi: 10.1007/s002130050366.
The purpose of these experiments was to examine the relationship of agonist relative efficacy to the pattern of tolerance and cross-tolerance to the morphine-like stimulus effects of three opioid agonists. Rats were trained to discriminate 3.2 mg/kg morphine from saline under fixed-ratio 15 schedule of food reinforcement. Morphine, nalbuphine, and fentanyl produced dose-dependent increases in morphine-like stimulus effects and decreases in response rates. Repeated treatment with 20 mg/kg per day morphine increased the ED50 for stimulus control by fentanyl, morphine, or nalbuphine two-, four-, or 40-fold, respectively. Repeated treatment with 64 mg/kg per day nalbuphine increased the ED50 for stimulus control for morphine by two-fold, but lower or higher treatment doses had no significant effect. Treatment with 100 mg/kg per day nalbuphine increased the ED50 for nalbuphine by six-fold. Repeated treatment with 0.22 mg/kg per day fentanyl increased the ED50 for stimulus control by fentanyl or morphine by approximately two-fold. Comparisons among treatment conditions suggested that magnitude of tolerance to morphine-like stimulus effects did not vary as an inverse function of the relative efficacy of the agonist used for repeated treatment. Rather repeated morphine and fentanyl treatments produced comparable tolerance, whereas repeated nalbuphine treatment did not evoke substantial tolerance. Comparisons within treatment conditions, however, suggested that magnitude of tolerance may vary inversely with relative efficacy of the agonist tested for morphine-like stimulus effects. During treatment with morphine or fentanyl, greater tolerance was observed to the morphine-like stimulus effects of the lower efficacy agonist relative to the higher efficacy agonist.
这些实验的目的是研究激动剂相对效价与对三种阿片类激动剂吗啡样刺激效应的耐受性和交叉耐受性模式之间的关系。大鼠在固定比率15的食物强化程序下接受训练，以区分3.2mg/kg吗啡和生理盐水。吗啡、纳布啡和芬太尼产生剂量依赖性的吗啡样刺激效应增加和反应率降低。每天用20mg/kg吗啡重复给药分别使芬太尼、吗啡或纳布啡刺激控制的半数有效剂量（ED50）增加2倍、4倍或40倍。每天用64mg/kg纳布啡重复给药使吗啡刺激控制的ED50增加2倍，但较低或较高的给药剂量没有显著影响。每天用100mg/kg纳布啡治疗使纳布啡的ED50增加6倍。每天用0.22mg/kg芬太尼重复给药使芬太尼或吗啡刺激控制的ED50增加约2倍。不同治疗条件之间的比较表明，对吗啡样刺激效应的耐受程度并不随重复治疗所用激动剂的相对效价呈反比变化。相反，重复给予吗啡和芬太尼产生了相当的耐受性，而重复给予纳布啡治疗并未引起显著的耐受性。然而，在治疗条件内的比较表明，耐受程度可能与测试吗啡样刺激效应的激动剂的相对效价呈反比。在用吗啡或芬太尼治疗期间，相对于高效价激动剂，观察到对低效价激动剂的吗啡样刺激效应有更大的耐受性。
