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The Journal of Neuroscience, November 12, 2003, 23(32):10331-10337

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Behavioral/Systems/Cognitive
Buprenorphine-Induced Antinociception Is Mediated by µ-Opioid Receptors and Compromised by Concomitant Activation of Opioid Receptor-Like Receptors

Kabirullah Lutfy,¹ Shoshana Eitan,¹ Camron D. Bryant,¹ Yu C. Yang,¹ Nazli Saliminejad,¹ Wendy Walwyn,¹ Brigitte L. Kieffer,² Hiroshi Takeshima,³ F. Ivy Carroll,⁴ Nigel T. Maidment,¹ and Christopher J. Evans¹

¹Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Neuropsychiatric Institute, Los Angeles, California 90024, ²Institut de Genetique et de Biologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique-Institut National de la Santé et de la Recherche Médicale-Université Louis Pasteur, 67404 Illkirch Cedex, France, ³Department of Biochemistry, Tohoku Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan, and ⁴Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194

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 µ-opioid receptors failed to exhibit antinociception after buprenorphine administration. Our results indicate that the antinociceptive effect of buprenorphine in mice is µ-opioid receptor-mediated yet severely compromised by concomitant activation of ORL-1 receptors.

Key words: antinociception; buprenorphine; J-113397; etorphine; morphine; orphanin FQ/nociceptin; ORL-1 receptors; µ-opioid receptors; knock-out mice; MAP kinase; tail-flick assay

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Received June 23, 2003; revised September 12, 2003; accepted September 18, 2003.

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