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μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence

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 responsiveness1,2,3. 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 β-arrestins4,5. Using a knockout mouse lacking β-arrestin-2 (βarr2-/-), we have assessed the contribution of desensitization of the μ-opioid receptor to the development of morphine antinociceptive tolerance and the subsequent onset of physical dependence. Here we show that in mice lacking β-arrestin-2, desensitization of the μ-opioid receptor does not occur after chronic morphine treatment, and that these animals fail to develop antinociceptive tolerance. However, the deletion of β-arrestin-2 does not prevent the chronic morphine-induced upregulation of adenylyl cyclase activity, a cellular marker of dependence, and the mutant mice still become physically dependent on the drug.

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Figure 1: Lack of morphine antinociceptive tolerance in βarr2-/- mice.
Figure 2: [35S]GTPγS binding to brainstem membranes from βarr2-/- and WT mice before and after chronic morphine treatment.
Figure 3: Lack of antinociceptive tolerance in βarr2-/- mice after 72 h of morphine-pellet implantation.
Figure 4: Naloxone-precipitated withdrawal after 72 h of morphine pellet implantation.
Figure 5: Adenylyl cyclase activity in WT and βarr2-/- mice after chronic morphine treatment.

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Acknowledgements

We thank S. Suter for care and genotyping of animals. R.R.G. is a visiting scientist from the Institute of Pharmacology, Russian Academy of Medical Sciences, Baltiyskaya 8, 125315 Moscow, Russia. M.G.C. and R.J.L. are Investigators of the Howard Hughes Medical Institute.

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Correspondence to Marc G. Caron.

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Bohn, L., Gainetdinov, R., Lin, FT. et al. μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence. Nature 408, 720–723 (2000). https://doi.org/10.1038/35047086

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