Picker M J, Cook C D
Department of Psychology, University of North Carolina at Chapel Hill 27599-3270, USA.
Behav Pharmacol. 1997 Jun;8(2-3):160-73.
The purpose of the present investigation was to examine the discriminative stimulus effects of opioids with activity at mu and kappa opioid receptors, in pigeons trained to discriminate the mu opioid fentanyl, the kappa opioid bremazocine and water in a three-choice discrimination task. The apparent pkB values obtained for naloxone as an antagonist of the stimulus effects of fentanyl were higher than those obtained against the bremazocine stimulus. The mu opioids morphine and l-methadone substituted for the fentanyl stimulus, the kappa opioids U50,488 and U69,593 substituted for the bremazocine stimulus, and the non-opioid pentobarbital failed to substitute for either the fentanyl or bremazocine stimulus. A series of opioids with activity at both the mu and kappa opioid receptor sites, including nalorphine, butorphanol, buprenorphine, nalbuphine, ethylketocyclazocine, (-)-ketocyclazocine, (-)-n-allylnormetazocine (NANM) and levallorphan, produced high levels of substitution for the fentanyl stimulus without producing appreciable levels of substitution for the bremazocine stimulus. At doses that did not substitute for the fentanyl stimulus, (-)-NANM, levallorphan, nalorphine and nalbuphine partially antagonized the bremazocine stimulus (i.e. produced responding on the water key). Butorphanol and buprenorphine also antagonized the bremazocine stimulus, although this effect was evidenced only at doses that substituted for the fentanyl stimulus. In contrast, even when tested up to doses that markedly decreased rates of responding, ethylketocyclazocine and (-)-ketocyclazocine failed to antagonize the bremazocine stimulus. The present findings indicate that in this three-choice task the fentanyl-like substitution patterns produced by opioids with activity at both the mu and kappa opioid receptors are similar to those reported in pigeons trained to discriminate either fentanyl or bremazocine from saline (i.e. two-choice tasks). In this task, however, the level of kappa antagonist activity evidenced by these opioids was considerably less than that obtained in pigeons trained to discriminate bremazocine from saline.
本研究的目的是在经过训练能在三项选择辨别任务中辨别μ阿片类芬太尼、κ阿片类布马佐辛和水的鸽子身上，研究对μ和κ阿片受体有活性的阿片类药物的辨别刺激效应。作为芬太尼刺激效应拮抗剂的纳洛酮所获得的表观pKB值高于针对布马佐辛刺激所获得的值。μ阿片类药物吗啡和左旋美沙酮替代了芬太尼刺激，κ阿片类药物U50,488和U69,593替代了布马佐辛刺激，而非阿片类药物戊巴比妥未能替代芬太尼或布马佐辛刺激。一系列对μ和κ阿片受体位点均有活性的阿片类药物，包括烯丙吗啡、布托啡诺、丁丙诺啡、纳布啡、乙基酮环唑辛、（-）-酮环唑辛、（-）-N-烯丙基去甲美沙酮（NANM）和左洛啡烷，对芬太尼刺激产生了高水平的替代，而对布马佐辛刺激未产生明显水平的替代。在未替代芬太尼刺激的剂量下，（-）-NANM、左洛啡烷、烯丙吗啡和纳布啡部分拮抗了布马佐辛刺激（即产生了在水键上的反应）。布托啡诺和丁丙诺啡也拮抗了布马佐辛刺激，尽管这种效应仅在替代芬太尼刺激的剂量下才得到证实。相比之下，即使测试到显著降低反应率的剂量，乙基酮环唑辛和（-）-酮环唑辛也未能拮抗布马佐辛刺激。目前的研究结果表明，在这项三项选择任务中，对μ和κ阿片受体均有活性的阿片类药物所产生的类似芬太尼的替代模式，与在经过训练能从盐水中辨别芬太尼或布马佐辛的鸽子（即两项选择任务）中所报道的模式相似。然而，在这项任务中，这些阿片类药物所显示的κ拮抗剂活性水平明显低于在经过训练能从盐水中辨别布马佐辛的鸽子中所获得的水平。
