Relative opioid efficacy is determined by the complements of the G protein-coupled receptor desensitization machinery.

Journal Article (Journal Article)

G protein-coupled receptor regulation by G protein-coupled receptor kinases and beta-arrestins can lead to desensitization and subsequent internalization of the receptor. In in vitro and cellular systems, beta-arrestins do not seem to play a major role in regulating micro opioid receptor (microOR) responsiveness. Removal of the betaarrestin2 (betaarr2) gene in mice leads paradoxically to enhanced and prolonged microOR-mediated antinociception. The betaarr2 knockout (betaarr2-KO) mice also fail to develop morphine antinociceptive tolerance in the hot-plate test, further indicating that the betaarr2 protein plays an essential role in microOR regulation in vivo. In this study, the contribution of betaarr2 to the regulation of the microOR was examined in both human embryonic kidney 293 cells and in betaarr2-KO mice after treatment with several opiate agonists. A green fluorescent protein tagged betaarr2 was used to assess receptor-betaarr2 interactions in living cells. Opiate agonists that induced robust betaarr2-green fluorescent protein translocation produced similar analgesia profiles in wild-type and betaarr2-KO mice, whereas those that do not promote robust betaarr2 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 beta-arrestins and microOR regulation wherein morphine-like agonists fail to promote efficient internalization and resensitization of the receptor.

Full Text

Duke Authors

Cited Authors

  • Bohn, LM; Dykstra, LA; Lefkowitz, RJ; Caron, MG; Barak, LS

Published Date

  • July 1, 2004

Published In

Volume / Issue

  • 66 / 1

Start / End Page

  • 106 - 112

PubMed ID

  • 15213301

International Standard Serial Number (ISSN)

  • 0026-895X

Digital Object Identifier (DOI)

  • 10.1124/mol.66.1.106


  • eng

Conference Location

  • United States