Lutfy Kabirullah, Eitan Shoshana, Bryant Camron D, Yang Yu C, Saliminejad Nazli, Walwyn Wendy, Kieffer Brigitte L, Takeshima Hiroshi, Carroll F Ivy, Maidment Nigel T, Evans Christopher J
Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Neuropsychiatric Institute, Los Angeles, California 90024, USA.
J Neurosci. 2003 Nov 12;23(32):10331-7. doi: 10.1523/JNEUROSCI.23-32-10331.2003.
Buprenorphine is a mixed opioid receptor agonist-antagonist used clinically for maintenance therapy in opiate addicts and pain management. Dose-response curves for buprenorphine-induced antinociception display ceiling effects or are bell shaped, which have been attributed to the partial agonist activity of buprenorphine at opioid receptors. Recently, buprenorphine has been shown to activate opioid receptor-like (ORL-1) receptors, also known as OP4 receptors. Here we demonstrate that buprenorphine, but not morphine, activates mitogen-activated protein kinase and Akt via ORL-1 receptors. Because the ORL-1 receptor agonist orphanin FQ/nociceptin blocks opioid-induced antinociception, we tested the hypothesis that buprenorphine-induced antinociception might be compromised by concomitant activation of ORL-1 receptors. In support of this hypothesis, the antinociceptive effect of buprenorphine, but not morphine, was markedly enhanced in mice lacking ORL-1 receptors using the tail-flick assay. Additional support for a modulatory role for ORL-1 receptors in buprenorphine-induced antinociception was that coadministration of J-113397, an ORL-1 receptor antagonist, enhanced the antinociceptive efficacy of buprenorphine in wild-type mice but not in mice lacking ORL-1 receptors. The ORL-1 antagonist also eliminated the bell-shaped dose-response curve for buprenorphine-induced antinociception in wild-type mice. Although buprenorphine has been shown to interact with multiple opioid receptors, mice lacking micro-opioid receptors failed to exhibit antinociception after buprenorphine administration. Our results indicate that the antinociceptive effect of buprenorphine in mice is micro-opioid receptor-mediated yet severely compromised by concomitant activation of ORL-1 receptors.
丁丙诺啡是一种混合阿片受体激动剂 - 拮抗剂，临床上用于阿片类成瘾者的维持治疗和疼痛管理。丁丙诺啡诱导的抗伤害感受的剂量 - 反应曲线呈现出天花板效应或呈钟形，这归因于丁丙诺啡在阿片受体上的部分激动剂活性。最近，丁丙诺啡已被证明可激活阿片受体样（ORL - 1）受体，也称为OP4受体。在此我们证明，丁丙诺啡而非吗啡，通过ORL - 1受体激活丝裂原活化蛋白激酶和Akt。由于ORL - 1受体激动剂孤啡肽/痛敏肽可阻断阿片类诱导的抗伤害感受，我们测试了以下假设：丁丙诺啡诱导的抗伤害感受可能会因ORL - 1受体的同时激活而受损。为支持这一假设，使用甩尾试验发现，在缺乏ORL - 1受体的小鼠中，丁丙诺啡而非吗啡的抗伤害感受作用显著增强。ORL - 1受体在丁丙诺啡诱导的抗伤害感受中起调节作用的进一步证据是，ORL - 1受体拮抗剂J - 113397的共同给药增强了野生型小鼠中丁丙诺啡的抗伤害感受效力，但在缺乏ORL - 1受体的小鼠中则没有。该ORL - 1拮抗剂还消除了野生型小鼠中丁丙诺啡诱导的抗伤害感受的钟形剂量 - 反应曲线。尽管丁丙诺啡已被证明可与多种阿片受体相互作用，但缺乏μ - 阿片受体的小鼠在给予丁丙诺啡后未表现出抗伤害感受。我们的结果表明，丁丙诺啡在小鼠中的抗伤害感受作用是由μ - 阿片受体介导的，但会因ORL - 1受体的同时激活而严重受损。
