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Agonist-Specific Regulation of µ-Opioid Receptor Desensitization and Recovery from Desensitization

Vollum Institute, Oregon Health and Science University, Portland, Oregon

Agonist-selective actions of opioids on the desensitization of µ-opioid receptors (MORs) have been well characterized, but few if any studies have examined agonist-dependent recovery from desensitization. The outward potassium current induced by several opioids was studied using whole-cell voltage-clamp recordings in locus ceruleus neurons. A brief application of the irreversible opioid antagonist β-chlornaltrexamine (β-CNA) was applied immediately after treatment of slices with saturating concentrations of opioid agonists. This approach permitted the measurement of desensitization and recovery from desensitization using multiple opioid agonists, including [Met]⁵enkephalin (ME), [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (DAMGO), etorphine, fentanyl, methadone, morphine, morphine-6-glucuronide, oxycodone, and oxymorphone. The results indicate that desensitization protects receptors from irreversible antagonism with β-CNA. The amount of desensitization was measured as the decrease in current during a 10-min application of a saturating agonist concentration and was a good predictor of the extent of receptor protection from irreversible inactivation with β-CNA. After desensitization with ME or DAMGO and treatment with β-CNA, there was an initial profound inhibition of MOR-induced current that recovered significantly after 45 min. There was, however, no recovery of MOR-mediated current with time after treatment with agonists that did not cause desensitization, such as oxycodone. These results demonstrate that desensitization prevents irreversible inactivation of receptors by β-CNA.

Address correspondence to: Dr. John T. Williams, Vollum Institute, L474, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97239. E-mail: williamj{at}ohsu.edu