• Article

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 mu-opioid receptors failed to

exhibit antinociception after buprenorphine administration. Our results

indicate that the antinociceptive effect of buprenorphine in mice is

mu-opioid receptor-mediated yet severely compromised by concomitant

activation of ORL-1 receptors.

Citation

Lutfy, K., Eitan, S., Bryant, CD., Yang, YC., Saliminejad, N., Walwyn, W., ... Evans, CJ. (2003). Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors. Journal of Neuroscience, 23(32), 10331-10337.