Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors.
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.
Lutfy
Kabirullah
K
Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Neuropsychiatric Institute, Los Angeles, California 90024, USA. klutfy@westernu.edu
Eitan
Shoshana
S
Bryant
Camron D
CD
Yang
Yu C
YC
Saliminejad
Nazli
N
Walwyn
Wendy
W
Kieffer
Brigitte L
BL
Takeshima
Hiroshi
H
Carroll
F Ivy
FI
Maidment
Nigel T
NT
Evans
Christopher J
CJ
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002047:Buprenorphine / Q000494:pharmacology*; D002478:Cells, Cultured; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018847:Opioid Peptides / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011957:Receptors, Opioid / Q000172:deficiency / Q000187:drug effects / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D000701:Analgesics, Opioid; D001562:Benzimidazoles; D002047:Buprenorphine; D020928:Mitogen-Activated Protein Kinases; D009020:Morphine; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010880:Piperidines; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C402921:J 113397; C494918:AKT1 protein, human