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The Journal of Neuroscience, June 3, 2009, 29(22):7341-7348; doi:10.1523/JNEUROSCI.3723-08.2009

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Cellular/Molecular
Buprenorphine Is a Weak Partial Agonist That Inhibits Opioid Receptor Desensitization

Michael S. Virk, Seksiri Arttamangkul, William T. Birdsong, and John T. Williams

Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239

Correspondence should be addressed to John T. Williams, Vollum Institute, L474, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Email: williamj{at}ohsu.edu

Buprenorphine is a weak partial agonist at µ-opioid receptors that is used for treatment of pain and addiction. Intracellular and whole-cell recordings were made from locus ceruleus neurons in rat brain slices to characterize the actions of buprenorphine. Acute application of buprenorphine caused a hyperpolarization that was prevented by previous treatment of slices with the irreversible opioid antagonist β-chlornaltrexamine (β-CNA) but was not reversed by a saturating concentration of naloxone. As expected for a partial agonist, subsaturating concentrations of buprenorphine decreased the [Met]5enkephalin (ME)-induced hyperpolarization or outward current. When the ME-induced current was decreased below a critical value, desensitization and internalization of µ-opioid receptors was eliminated. The inhibition of desensitization by buprenorphine was not the result of previous desensitization, slow dissociation from the receptor, or elimination of receptor reserve. Treatment of slices with subsaturating concentrations of etorphine, methadone, oxymorphone, or β-CNA also reduced the current induced by ME but did not block ME-induced desensitization. Treatment of animals with buprenorphine for 1 week resulted in the inhibition of the current induced by ME and a block of desensitization that was not different from the acute application of buprenorphine to brain slices. These observations show the unique characteristics of buprenorphine and further demonstrate the range of agonist-selective actions that are possible through G-protein-coupled receptors.

Received Aug. 6, 2008; revised May 4, 2009; accepted May 5, 2009.

Correspondence should be addressed to John T. Williams, Vollum Institute, L474, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Email: williamj{at}ohsu.edu






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