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Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence

Academic Article
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Overview

authors

  • Bohn, Laura
  • Gainetdinov, R. R.
  • Lin, F. T.
  • Lefkowitz, R. J.
  • Caron, M. G.

publication date

  • December 2000

journal

  • Nature  Journal

abstract

  • Morphine is a powerful pain reliever, but also a potent inducer of tolerance and dependence. The development of opiate tolerance occurs on continued use of the drug such that the amount of drug required to elicit pain relief must be increased to compensate for diminished responsiveness. In many systems, decreased responsiveness to agonists has been correlated with the desensitization of G-protein-coupled receptors. In vitro evidence indicates that this process involves phosphorylation of G-protein-coupled receptors and subsequent binding of regulatory proteins called beta-arrestins. Using a knockout mouse lacking beta-arrestin-2 (beta arr2-/-), we have assessed the contribution of desensitization of the mu-opioid receptor to the development of morphine antinociceptive tolerance and the subsequent onset of physical dependence. Here we show that in mice lacking beta-arrestin-2, desensitization of the mu-opioid receptor does not occur after chronic morphine treatment, and that these animals fail to develop antinociceptive tolerance. However, the deletion of beta-arrestin-2 does not prevent the chronic morphine-induced up-regulation of adenylyl cyclase activity, a cellular marker of dependence, and the mutant mice still become physically dependent on the drug.

subject areas

  • Adenylyl Cyclases
  • Analgesics, Opioid
  • Animals
  • Arrestins
  • Brain Stem
  • Drug Implants
  • Drug Tolerance
  • GTP-Binding Proteins
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Membranes
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Morphine
  • Morphine Dependence
  • Mutation
  • Receptors, Opioid, mu
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Identity

International Standard Serial Number (ISSN)

  • 0028-0836

PubMed ID

  • 11130073
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Additional Document Info

start page

  • 720

end page

  • 723

volume

  • 408

issue

  • 6813

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