Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects

A. Kliewer, F. Schmiedel, S. Sianati, A. Bailey, J. T. Bateman, E. S. Levitt, J. T. Williams, M. J. Christie and S. Schulz ()
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A. Kliewer: Jena University Hospital, Friedrich-Schiller-University
F. Schmiedel: Jena University Hospital, Friedrich-Schiller-University
S. Sianati: University of Sydney
A. Bailey: St George’s University of London
J. T. Bateman: University of Florida
E. S. Levitt: University of Florida
J. T. Williams: Oregon Health and Science University
M. J. Christie: University of Sydney
S. Schulz: Jena University Hospital, Friedrich-Schiller-University

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Opioid analgesics are powerful pain relievers; however, over time, pain control diminishes as analgesic tolerance develops. The molecular mechanisms initiating tolerance have remained unresolved to date. We have previously shown that desensitization of the μ-opioid receptor and interaction with β-arrestins is controlled by carboxyl-terminal phosphorylation. Here we created knockin mice with a series of serine- and threonine-to-alanine mutations that render the receptor increasingly unable to recruit β-arrestins. Desensitization is inhibited in locus coeruleus neurons of mutant mice. Opioid-induced analgesia is strongly enhanced and analgesic tolerance is greatly diminished. Surprisingly, respiratory depression, constipation, and opioid withdrawal signs are unchanged or exacerbated, indicating that β-arrestin recruitment does not contribute to the severity of opioid side effects and, hence, predicting that G-protein-biased µ-agonists are still likely to elicit severe adverse effects. In conclusion, our findings identify carboxyl-terminal multisite phosphorylation as key step that drives acute μ-opioid receptor desensitization and long-term tolerance.

Date: 2019
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DOI: 10.1038/s41467-018-08162-1

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