{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T01:02:16Z","timestamp":1789434136508,"version":"build-2803163510"},"reference-count":103,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2012,2,22]],"date-time":"2012-02-22T00:00:00Z","timestamp":1329868800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2012,3]]},"abstract":"<jats:p>\n                    Agonists acting on \u00b5\u2010opioid receptors (MOR) are very effective analgesics but cause tolerance during long\u2010term or repeated exposure. Intensive efforts have been made to find novel opioid agonists that are efficacious analgesics but can elude the signalling events that cause tolerance. \u00b5\u2010Opioid agonists differentially couple to downstream signalling mechanisms. Some agonists, such as enkephalins,\n                    <jats:sc>d<\/jats:sc>\n                    \u2010Ala(2),\n                    <jats:italic>N<\/jats:italic>\n                    \u2010Me\u2010Phe(4),Gly(5)\u2010ol]\u2010enkephalin (DAMGO), methadone and sufentanyl are efficacious at mediating G\u2010protein and effector coupling, as well as triggering MOR regulatory events that include MOR phosphorylation, \u03b2\u2010arrestin binding, receptor endocytosis and recycling. By contrast, morphine and closely related alkaloids can mediate efficacious MOR\u2013effector coupling but poorly trigger receptor regulation. Several models have been proposed to relate differential MOR regulation by different opioids with their propensity to cause tolerance. Most are based on dogma that \u03b2\u2010arrestin\u20102 (\u03b2arr\u20102) binding causes MOR desensitization and\/or that MOR endocytosis and recycling are required for receptor resensitization. This review will examine some of these notions in light of recent evidence establishing that MOR dephosphorylation and resensitization do not require endocytosis. Recent evidence from opioid\u2010treated animals also suggests that impaired MOR\u2013effector coupling is driven, at least in part, by enhanced desensitization, as well as impaired resensitization that appears to be \u03b2arr\u20102 dependent. Better understanding of how chronic exposure to opioids alters receptor regulatory mechanisms may facilitate the development of effective analgesics that produce limited tolerance.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>LINKED ARTICLES<\/jats:bold>\n                    This article is part of a themed section on the Molecular Pharmacology of G Protein\u2010Coupled Receptors (GPCRs). To view the other articles in this section visit\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/dx.doi.org\/10.1111\/bph.2012.165.issue-6\">http:\/\/dx.doi.org\/10.1111\/bph.2012.165.issue\u20106<\/jats:ext-link>\n                    . 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