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Relative Opioid Efficacy Is Determined by the Complements of the G Protein-Coupled Receptor Desensitization Machinery

Departments of Pharmacology and Psychiatry, the Ohio State University College of Medicine and Public Health, Columbus, Ohio (L.M.B.); Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (L.A.D.); Departments of Cell Biology (M.G.C., L.S.B.), Biochemistry (R.J.L.), and Medicine (R.J.L., M.G.C.), Duke University Medical Center, Howard Hughes Medical Institute Laboratories, Durham, North Carolina

G protein-coupled receptor regulation by G protein-coupled receptor kinases and -arrestins can lead to desensitization and subsequent internalization of the receptor. In in vitro and cellular systems, -arrestins do not seem to play a major role in regulating µ opioid receptor (µOR) responsiveness. Removal of the arrestin2 (arr2) gene in mice leads paradoxically to enhanced and prolonged µOR-mediated antinociception. The arr2 knockout (arr2-KO) mice also fail to develop morphine antinociceptive tolerance in the hot-plate test, further indicating that the arr2 protein plays an essential role in µOR regulation in vivo. In this study, the contribution of arr2 to the regulation of the µOR was examined in both human embryonic kidney 293 cells and in arr2-KO mice after treatment with several opiate agonists. A green fluorescent protein tagged arr2 was used to assess receptor-arr2 interactions in living cells. Opiate agonists that induced robust arr2-green fluorescent protein translocation produced similar analgesia profiles in wild-type and arr2-KO mice, whereas those that do not promote robust arr2 recruitment, such as morphine and heroin, produce enhanced analgesia in vivo. In this report, we present a rationale to explain the seemingly paradoxical relationship between -arrestins and µOR regulation wherein morphine-like agonists fail to promote efficient internalization and resensitization of the receptor.

Received November 11, 2003; accepted April 2, 2004.

Address correspondence to: Marc G. Caron, Box 3287, CARL Bldg., Duke University Medical Center, Durham, NC, 27710. E-mail: m.caron{at}cellbio.duke.edu

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