Suzuki T, Funada M, Narita M, Misawa M, Nagase H
Department of Pharmacology, Hoshi University, Tokyo, Japan.
Brain Res. 1993 Jan 29;602(1):45-52. doi: 10.1016/0006-8993(93)90239-j.
The role of mu opioid receptor subtypes, mu 1 and mu 2, in morphine-conditioned place preference was examined using ddY and mu 1 opioid receptor-deficient CXBK mice. In ddY mice, the mu receptor agonist morphine caused a dose-related preference for the drug-associated place, but the kappa agonist U-50,488H produced a dose-related place aversion. These results demonstrated that the mouse is available for place preference conditioning using opioids. Under this condition, the influence of pretreatment with the selective mu 1 opioid receptor antagonist naloxonazine on morphine-induced place preference was investigated in ddY mice. Although pretreatment with the selective mu 1 antagonist naloxonazine (35 mg/kg, s.c.) did not modify the morphine-induced place preference, pretreatment with the selective mu antagonist beta-funaltrexamine (beta-FNA 10 mg/kg, s.c.) eliminated the appetitive effect of morphine. Furthermore, morphine (1-5 mg/kg, s.c.) produced a dose-related preference for the drug-associated place in CXBK mice. These findings suggest that the morphine-induced conditioned place preference may be mediated by naloxonazine-insensitive sites (mu 2 opioid receptors). In addition, chronic infusion of the dopamine D1 antagonist SCH23390 (1.0 mg/kg/day) during the conditioning sessions eliminated the morphine-induced place preference in CXBK mice. Similarly, morphine combined with naloxonazine failed to produce the place preference in ddY mice chronically treated with SCH23390. The blocking effect of SCH23390 on the morphine-conditioned place preference suggests that mu 2 receptors may regulate the dopaminergic system, especially dopamine D1 receptors, and are also involved in the reinforcing effects of morphine.
使用ddY小鼠和缺乏μ1阿片受体的CXBK小鼠，研究了μ阿片受体亚型μ1和μ2在吗啡条件性位置偏爱中的作用。在ddY小鼠中，μ受体激动剂吗啡引起对药物相关位置的剂量依赖性偏爱，但κ激动剂U-50,488H产生剂量依赖性位置厌恶。这些结果表明，小鼠可用于阿片类药物的位置偏爱条件反射实验。在此条件下，研究了在ddY小鼠中，选择性μ1阿片受体拮抗剂纳洛酮嗪预处理对吗啡诱导的位置偏爱的影响。虽然选择性μ1拮抗剂纳洛酮嗪（35mg/kg，皮下注射）预处理并未改变吗啡诱导的位置偏爱，但选择性μ拮抗剂β-氟纳曲酮（β-FNA 10mg/kg，皮下注射）预处理消除了吗啡的奖赏效应。此外，吗啡（1-5mg/kg，皮下注射）在CXBK小鼠中产生了对药物相关位置的剂量依赖性偏爱。这些发现表明，吗啡诱导的条件性位置偏爱可能由对纳洛酮嗪不敏感的位点（μ2阿片受体）介导。此外，在条件反射实验期间慢性输注多巴胺D1拮抗剂SCH23390（1.0mg/kg/天）消除了CXBK小鼠中吗啡诱导的位置偏爱。同样，吗啡与纳洛酮嗪联合使用未能在长期接受SCH23390治疗的ddY小鼠中产生位置偏爱。SCH23390对吗啡条件性位置偏爱的阻断作用表明，μ2受体可能调节多巴胺能系统，尤其是多巴胺D1受体，并且也参与吗啡的强化作用。
