Buprenorphine-Induced Antinociception Is Mediated by μ-Opioid Receptors and Compromised by Concomitant Activation of Opioid Receptor-Like Receptors
Open accessAbstract
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.
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The fact that a bell-shaped curve was not observed in the tail withdrawal test may be related to differences in the intensity of the noxious stimulus.
“The fact that a bell-shaped curve was not observed in the tail withdrawal test may be related to differences in the intensity of the noxious stimulus (Bilel et al., 2022; Lutfy et al., 2003).”
From Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization (2024) · cites this paper as Lutfy et al., 2003
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- Authors
- Lutfy, K., Eitan, S., Bryant, C. D., Yang, Y. C., Saliminejad, N., Walwyn, W., Kieffer, B. L., Takeshima, H., Carroll, F. I., Maidment, N. T., & Evans, C. J.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-11-12
- Volume
- 23
- Issue
- 32
- Pages
- 10331-10337
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6741014
- OpenAlex
- W4296759769
- Cited by
- 211
- References
- 47
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 10 · 2023: 11 · 2022: 12 · 2021: 12 · 2020: 10 · 2019: 11 · 2018: 10 · 2017: 12 · 2016: 6 · 2015: 8 · 2014: 10 · 2013: 16 · 2012: 7
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- HAL (submittedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health (DA05010)
- National Institute on Drug Abuse (P50DA005010, Z01DA000411, DA 09045, DA05010, R01DA009045, DA00411, DA-09359, R01DA009359)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Keywords
- buprenorphine, antinociception, mu-opioid receptor, nociceptin/orphanin FQ, bell-shaped dose-response, ceiling effect, mitogen-activated protein kinase, Akt, J-113397, morphine, opioid receptor interaction, analgesia
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