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

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Abstract
G protein-coupled receptor regulation by G protein-coupled receptor kinases and β-arrestins can lead to desensitization and subsequent internalization of the receptor. In in vitro and cellular systems, β-arrestins do not seem to play a major role in regulating μ opioid receptor (μOR) responsiveness. Removal of the βarrestin2 (βarr2) gene in mice leads paradoxically to enhanced and prolonged μOR-mediated antinociception. The βarr2 knockout (βarr2-KO) mice also fail to develop morphine antinociceptive tolerance in the hot-plate test, further indicating that the βarr2 protein plays an essential role in μOR regulation in vivo. In this study, the contribution of βarr2 to the regulation of the μOR was examined in both human embryonic kidney 293 cells and in βarr2-KO mice after treatment with several opiate agonists. A green fluorescent protein tagged βarr2 was used to assess receptor-βarr2 interactions in living cells. Opiate agonists that induced robust βarr2-green fluorescent protein translocation produced similar analgesia profiles in wild-type and βarr2-KO mice, whereas those that do not promote robust βarr2 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 β-arrestins and μOR regulation wherein morphine-like agonists fail to promote efficient internalization and resensitization of the receptor.