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

Publication ,  Journal Article
Bohn, LM; Gainetdinov, RR; Lin, FT; Lefkowitz, RJ; Caron, MG
Published in: Nature
December 7, 2000

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.

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Published In

Nature

DOI

ISSN

0028-0836

Publication Date

December 7, 2000

Volume

408

Issue

6813

Start / End Page

720 / 723

Location

England

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • Receptors, Opioid, mu
  • Mutation
  • Morphine Dependence
  • Morphine
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Membranes
 

Citation

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Bohn, L. M., Gainetdinov, R. R., Lin, F. T., Lefkowitz, R. J., & Caron, M. G. (2000). Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature, 408(6813), 720–723. https://doi.org/10.1038/35047086
Bohn, L. M., R. R. Gainetdinov, F. T. Lin, R. J. Lefkowitz, and M. G. Caron. “Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence.Nature 408, no. 6813 (December 7, 2000): 720–23. https://doi.org/10.1038/35047086.
Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, Caron MG. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature. 2000 Dec 7;408(6813):720–3.
Bohn, L. M., et al. “Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence.Nature, vol. 408, no. 6813, Dec. 2000, pp. 720–23. Pubmed, doi:10.1038/35047086.
Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, Caron MG. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature. 2000 Dec 7;408(6813):720–723.
Journal cover image

Published In

Nature

DOI

ISSN

0028-0836

Publication Date

December 7, 2000

Volume

408

Issue

6813

Start / End Page

720 / 723

Location

England

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • Receptors, Opioid, mu
  • Mutation
  • Morphine Dependence
  • Morphine
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Membranes