Effects of Direct- and Indirect-Acting Serotonin Receptor Agonists on the Antinociceptive and Discriminative Stimulus Effects of Morphine in Rhesus Monkeys
Effects of Direct- and Indirect-Acting Serotonin Receptor Agonists on the Antinociceptive and Discriminative Stimulus Effects of Morphine in Rhesus Monkeys
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DOI：
10.1038/npp.2010.232
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发表时间：
2011-04-01
影响因子：
7.6
通讯作者：
France, Charles P.
中科院分区：
文献类型：
--
作者：
Li, Jun-Xu;Koek, Wouter;France, Charles P.
5-羟色胺能（5-HT）系统调节疼痛，作用于5-HT系统的药物与阿片类药物一起用于治疗疼痛。本研究探讨了5-羟色胺受体激动剂对猴子吗啡的抗痛觉性和区别性刺激作用的影响。吗啡增加尾戒断潜伏期呈剂量相关；单独使用5-羟色胺受体激动剂会增加在50℃而不是55℃水中的脱尾潜伏期。当猴子接受间接作用（芬氟拉明）或直接作用（8-OH-DPAT、F13714、丁螺环酮、喹帕嗪、DOM和2C-T-7）激动剂时，吗啡的抗感觉作用较小。选择性5-HT1A （WAY100635）和5-HT2A （MDL100907）受体拮抗剂证实了5-HT受体亚型在这些相互作用中的作用。5-HT药物均不具有吗啡样的区别刺激作用；然而，芬氟拉明和5-HT2A受体激动剂会减弱吗啡的鉴别刺激作用，而MDL100907可以阻止这种减弱。5-HT1A受体激动剂不改变吗啡的鉴别刺激作用。因此，5-羟色胺受体激动剂在抗痛觉试验中增加吗啡的效力，即使在5-羟色胺激动剂本身没有作用的条件下（即55℃的水），在药物鉴别试验中也不会增加（在某些情况下会降低）吗啡的效力。5-HT2A受体激动剂在不影响操作性反应率的剂量下增加吗啡的抗痛觉效力，而5-HT1A受体激动剂仅在消除操作性反应的剂量下增加吗啡的效力。这些数据表明，选择性作用于5-HT受体亚型的药物可能有助于改善阿片类药物治疗疼痛的使用。神经精神药理学（2011）36,940-949；doi: 10.1038 / npp.2010.232;2011年1月5日在线发布
Serotonergic (5-HT) systems modulate pain, and drugs acting on 5-HT systems are used with opioids to treat pain. This study examined the effects of 5-HT receptor agonists on the antinociceptive and discriminative stimulus effects of morphine in monkeys. Morphine increased tail-withdrawal latency in a dose-related manner; 5-HT receptor agonists alone increased tail-withdrawal latency at 50 degrees C but not 55 degrees C water. The antinociceptive effects of morphine occurred with smaller doses when monkeys received an indirect-acting (fenfluramine) or direct acting (8-OH-DPAT, F13714, buspirone, quipazine, DOM, and 2C-T-7) agonist. The role of 5-HT receptor subtypes in these interactions was confirmed with selective 5-HT1A (WAY100635) and 5-HT2A (MDL100907) receptor antagonists. None of the 5-HT drugs had morphine-like discriminative stimulus effects; however, fenfluramine and 5-HT2A receptor agonists attenuated the discriminative stimulus effects of morphine and this attenuation was prevented by MDL100907. The 5-HT1A receptor agonists did not alter the discriminative stimulus effects of morphine. Thus, 5-HT receptor agonists increase the potency of morphine in an assay of antinociception, even under conditions where 5-HT agonists are themselves without effect (ie, 55 degrees C water), without increasing (and in some cases decreasing) the potency of morphine in a drug discrimination assay. Whereas 5-HT2A receptor agonists increase the potency of morphine for antinociception at doses that have no effect on the rate of operant responding, 5-HT1A receptor agonists increase the potency of morphine only at doses that eliminate operant responding. These data suggest that drugs acting selectively on 5-HT receptor subtypes could help to improve the use of opioids for treating pain. Neuropsychopharmacology (2011) 36, 940-949; doi:10.1038/npp.2010.232; published online 5 January 2011