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The contribution of acute <jats:italic>\u03bc<\/jats:italic>\u2010opioid receptor regulatory mechanisms to the development of analgesic tolerance or physical dependence are unknown, and even the mechanisms underlying relatively rapid receptor desensitization in single cells are unresolved. To a large degree, the uncertainty surrounding the mechanisms and consequences of short\u2010term regulation of <jats:italic>\u03bc<\/jats:italic>\u2010opioid receptors in single cells arises from the limitations in the experimental design in many of the studies that have investigated these events. Receptor overexpression and use of assays in which regulatory mechanisms are likely to blunt control determinations have led to measurements of opioid receptor activity that are likely to be insensitive to receptor uncoupling. Together with uncertainties concerning molecular details of <jats:italic>\u03bc<\/jats:italic>\u2010opioid receptor interactions with potential regulatory molecules such as G protein\u2010coupled receptor kinases and arrestins, we are left with an incomplete picture crudely copied from the well\u2010worked\u2010out regulatory schema for <jats:italic>\u03b2<\/jats:italic><jats:sub>2<\/jats:sub>\u2010adrenoceptors. As a consequence, suggestions that clinically relevant <jats:italic>\u03bc<\/jats:italic>\u2010opioid receptor agonists may have different propensities to produce tolerance and dependence that arise from their differential recruitment of regulatory mechanisms are premature, and have not yet been appropriately assessed, nor explained in the context of a thoroughly established regulatory scheme. In this commentary, we outline the experimental limitations that have given rise to conflicting ideas about how <jats:italic>\u03bc<\/jats:italic>\u2010opioid receptors are regulated, and identify the issues we feel still need to be addressed before we can understand why morphine promotes receptor trafficking differently to other opioids.<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2004) <jats:bold>143<\/jats:bold>, 685\u2013696. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0705938\">10.1038\/sj.bjp.0705938<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0705938","type":"journal-article","created":{"date-parts":[[2004,11,11]],"date-time":"2004-11-11T16:33:07Z","timestamp":1100190787000},"page":"685-696","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":97,"title":["<i>\u03bc<\/i>\u2010Opioid receptor desensitization: Is morphine different?"],"prefix":"10.1111","volume":"143","author":[{"given":"Mark","family":"Connor","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peregrine B","family":"Osborne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MacDonald J","family":"Christie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,2,17]]},"reference":[{"key":"e_1_2_6_2_1","first-page":"116","article-title":"Stimulation of guanosine\u20105\u2032\u2010O\u2010(3\u2010[35S]thio)triphosphate binding in digitonin\u2010permeabilized C6 rat glioma cells: evidence for an organized association of \u03bc\u2010opioid receptors and G protein","volume":"298","author":"ALT A.","year":"2001","journal-title":"J. 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