Received for publication October 26, 2007.
Revised December 17, 2007.
Accepted for publication January 14, 2008.

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

Abstract

Agonist-selective actions of opioids on the desensitization of µ-opioid receptors (MOR) have been well characterized, but few if any studies that 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 coeruleus (LC) neurons. A brief application of the irreversible opioid antagonist, -chlornaltrexamine (-CNA), was applied immediately following 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), DAMGO, etorphine, fentanyl, methadone, morphine, morphine-6-glucuronide, oxycodone and oxymorphone. The results indicate that desensitization protects receptors from irreversible antagonism with -CNA. The amount of desensitization was measured as the decline 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 -CNA. Following desensitization with ME or DAMGO and treatment with -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 -CNA.

Key words: Adrenergic, Neuropeptides, Opioid, Gi family, Desensitization/uncoupling, Sequestration/Internalization, Recycling, Opioids

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