Adams J U, Holtzman S G
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322.
Pharmacol Biochem Behav. 1991 Jan;38(1):195-200. doi: 10.1016/0091-3057(91)90610-e.
Selective cross-tolerance is often used as evidence to differentiate opioid receptor subtypes. We used this strategy to study operant behavioral effects of the opioid peptides, [D-Ala2, NMePhe4, Gly-ol5]enkephalin (DAGO), [D-Pen2.5]-enkephalin (DPDPE) and dynorphin, agonists highly selective for mu, delta, and kappa receptors, respectively. Food-deprived rats were trained to lever-press on a fixed-interval 3-min schedule of food-reinforcement. Time-effect and dose-effect curves were generated for each of the peptides, as well as for morphine, administered ICV, 5 min prior to the 1-h operant session. Experiments were performed on untreated subjects and on subjects receiving chronic infusion of morphine (10 mg/kg/day) from osmotic pumps. In untreated animals, morphine and the mu-selective peptide, DAGO, induced relatively long-lasting dose-related decreases in responding, whereas the non-mu agonists, DPDPE and dynorphin, induced only transient effects: response rates increased at low doses and decreased at high doses. Animals receiving chronic morphine infusion were tolerant to the rate-decreasing effects of morphine and DAGO; ED50s increased by factors of 8 and 6, respectively. There was some evidence of cross-tolerance to DPDPE and of sensitization to dynorphin in the morphine-maintained animals.
选择性交叉耐受性常被用作区分阿片受体亚型的证据。我们采用这种策略来研究阿片肽、[D - 丙氨酸2，N - 甲基苯丙氨酸4，甘醇5]脑啡肽（DAGO）、[D - 青霉胺2，5] - 脑啡肽（DPDPE）和强啡肽的操作性行为效应，这些激动剂分别对μ、δ和κ受体具有高度选择性。将食物剥夺的大鼠训练为在固定间隔3分钟的食物强化时间表上按压杠杆。在1小时操作性实验前5分钟，通过脑室内注射（ICV）为每种肽以及吗啡生成时间效应和剂量效应曲线。实验在未处理的动物以及从渗透泵接受吗啡慢性输注（10mg/kg/天）的动物身上进行。在未处理的动物中，吗啡和μ选择性肽DAGO诱导相对持久的剂量相关反应减少，而非μ激动剂DPDPE和强啡肽仅诱导短暂效应：低剂量时反应率增加，高剂量时反应率降低。接受吗啡慢性输注的动物对吗啡和DAGO的降低反应率效应产生耐受性；半数有效剂量（ED50）分别增加了8倍和6倍。在吗啡维持的动物中，有一些对DPDPE交叉耐受性和对强啡肽敏化的证据。
