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With acute administration, morphine is unlike many other opioid agonists in that it does not mediate robust acute desensitization or induce receptor trafficking. This study compares \u03bc-opioid receptor desensitization and trafficking in brain slices taken from rats treated for 6\u20137 d with a range of doses of morphine (60, 30, and 15 mg \u00b7 kg<jats:sup>\u22121<\/jats:sup>\u00b7 d<jats:sup>\u22121<\/jats:sup>) and methadone (60, 30, and 5 mg \u00b7 kg<jats:sup>\u22121<\/jats:sup>\u00b7 d<jats:sup>\u22121<\/jats:sup>) applied by subcutaneous implantation of osmotic minipumps. Mice were treated with 45 mg \u00b7 kg<jats:sup>\u22121<\/jats:sup>\u00b7 d<jats:sup>\u22121<\/jats:sup>. In morphine-treated animals, recovery from acute [Met]<jats:sup>5<\/jats:sup>enkephalin-induced desensitization and receptor recycling was diminished. In contrast, recovery and recycling were unchanged in slices from methadone-treated animals. Remarkably the reduced recovery from desensitization and receptor recycling found in slices from morphine-treated animals were not observed in animals lacking \u03b2-arrestin-2. Furthermore, pharmacological inhibition of G-protein receptor kinase 2 (GRK2), although not affecting the ability of [Met]<jats:sup>5<\/jats:sup>enkephalin to induce desensitization, acutely reversed the delay in recovery from desensitization produced by chronic morphine treatment. These results characterize a previously unidentified function of the GRK\/arrestin system in mediating opioid regulation in response to chronic morphine administration. They also suggest that the GRK\/arrestin system, rather than serving as a primary mediator of acute desensitization, controls recovery from desensitization by regulating receptor reinsertion to the plasma membrane after chronic treatment with morphine. The sustained GRK\/arrestin-dependent desensitization is another way in which morphine and methadone are distinguished.<\/jats:p>","DOI":"10.1523\/jneurosci.4874-10.2011","type":"journal-article","created":{"date-parts":[[2011,3,23]],"date-time":"2011-03-23T16:53:58Z","timestamp":1300899238000},"page":"4434-4443","source":"Crossref","is-referenced-by-count":82,"title":["Recovery from \u03bc-Opioid Receptor Desensitization after Chronic Treatment with Morphine and Methadone"],"prefix":"10.1523","volume":"31","author":[{"given":"Nidia","family":"Quillinan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine K.","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Virk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"von 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