title: Agonist-specific regulation of mu-opioid receptor desensitization and recovery from desensitization.
abstract: Agonist-selective actions of opioids on the desensitization of mu-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 beta-chlornaltrexamine (beta-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](5)enkephalin (ME), [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), etorphine, fentanyl, methadone, morphine, morphine-6-glucuronide, oxycodone, and oxymorphone. The results indicate that desensitization protects receptors from irreversible antagonism with beta-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 beta-CNA. After desensitization with ME or DAMGO and treatment with beta-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 beta-CNA.
authors.affiliation: Vollum Institute, L474, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97239. williamj@ohsu.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Virk
authors.forename: John T
authors.initials: JT
authors.lastname: Williams
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D004594:Electrophysiology; D004745:Enkephalins / Q000494:pharmacology; D005048:Etorphine / Q000494:pharmacology; D005283:Fentanyl / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D010111:Oxymorphone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D004745:Enkephalins; D017450:Receptors, Opioid, mu; D005048:Etorphine; D009271:Naltrexone; C017120:chlornaltrexamine; D010111:Oxymorphone; D005283:Fentanyl