Picker M J, Doty P, Negus S S, Mattox S R, Dykstra L A
Department of Psychology, University of North Carolina, Chapel Hill.
J Pharmacol Exp Ther. 1990 Jul;254(1):13-22.
By using a two-lever drug discrimination task, four groups of rats were trained to discriminate either a low (3.0 mg/kg) and a high (5.6 mg/kg) training dose of the kappa opioid agonist U50,488 [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolindinyl)cyclohexyl] benzeneacetamine methanesulfonate hydrate] or a low (3.0 mg/kg) and a high (10 mg/kg) training dose of the mu opioid agonist morphine from water. The stimulus effects of the high training dose of U50,488 were shared by the kappa agonists bremazocine and ethylketocyclazocine (i.e., these drugs produced at least 80% drug-appropriate responding), but not by the mu agonists morphine, fentanyl and l-methadone or the nonopioid compounds d-amphetamine, pentobarbital and phencyclidine. Conversely, the stimulus effects of the high training dose of morphine were shared by other mu agonists, but not by the kappa agonists or the nonopioid compounds examined. Similarities in the stimulus effects of morphine and U50,488 occurred, however, when mu and kappa agonists were examined in rats trained to discriminate relatively low training doses of morphine or U50,488 from water. At the low training dose of morphine, complete substitution was obtained with the mu agonists tested as well as the kappa agonist ketocyclazocine. In these rats, intermediate (approximately 70% drug-appropriate responding) levels of substitution were obtained with the kappa agonists bremazocine and ethyylketocyclazocine. Similarly, at the low training dose of U50,488 both the mu and kappa agonists examined substituted completely. Asymmetrical substitution occurred between U50,488 and morphine at the low training doses, with morphine substituting completely for the low training dose of U50,488 and U50,488 failing to substitute for the low training dose of morphine. The rank order of potency for naloxone as an antagonist of the stimulus effects of morphine and U50,488 was; 3.0 mg/kg of morphine greater than 10 mg/kg of morphine greater than 3.0 mg/kg of U50,488 = 5.6 mg/kg of U50,488. The present results indicate that training dose is an important determinant of the different levels of cross-substitution obtained between mu and kappa agonists, and that a greater pharmacological specificity of drug-induced discriminative stimuli can be obtained when relatively high training doses of mu and kappa opioid agonists are used to establish the discrimination.
通过使用双杠杆药物辨别任务，四组大鼠被训练以区分κ阿片受体激动剂U50,488 [反式-3,4-二氯-N-甲基-N-[2-(1-吡咯烷基)环己基]苯乙胺甲磺酸盐一水合物]的低（3.0毫克/千克）和高（5.6毫克/千克）训练剂量，或μ阿片受体激动剂吗啡的低（3.0毫克/千克）和高（10毫克/千克）训练剂量与水。U50,488高训练剂量的刺激效应与κ激动剂布马佐辛和乙基酮环唑辛相同（即这些药物产生至少80%的药物适应性反应），但与μ激动剂吗啡、芬太尼和左美沙酮或非阿片类化合物右旋苯丙胺、戊巴比妥和苯环己哌啶不同。相反，吗啡高训练剂量的刺激效应与其他μ激动剂相同，但与所检测的κ激动剂或非阿片类化合物不同。然而，当在训练以区分相对低剂量的吗啡或U50,488与水的大鼠中检测μ和κ激动剂时，吗啡和U50,488的刺激效应出现了相似性。在吗啡的低训练剂量下，所测试的μ激动剂以及κ激动剂酮环唑辛都能完全替代。在这些大鼠中，κ激动剂布马佐辛和乙基酮环唑辛能产生中等程度（约70%的药物适应性反应）的替代。同样，在U50,488的低训练剂量下，所检测的μ和κ激动剂都能完全替代。在低训练剂量下，U50,488和吗啡之间出现了不对称替代，吗啡能完全替代U50,488的低训练剂量，而U50,488不能替代吗啡的低训练剂量。纳洛酮作为吗啡和U50,488刺激效应拮抗剂的效价顺序为：3.0毫克/千克的吗啡＞10毫克/千克的吗啡＞3.0毫克/千克的U50,488 = 5.6毫克/千克的U50,488。目前的结果表明，训练剂量是μ和κ激动剂之间获得不同程度交叉替代的重要决定因素，并且当使用相对高剂量的μ和κ阿片受体激动剂来建立辨别时，可以获得更高的药物诱导辨别刺激的药理学特异性。
