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Nat Commun. 2019 Jan 21;10(1):367. doi: 10.1038/s41467-018-08162-1.

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

Author information

1
Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, 07747, Jena, Germany.
2
Discipline of Pharmacology, School of Medical Sciences, University of Sydney, NSW, 2006, Australia.
3
Institute of Medical and Biomedical Education, St George's University of London, London, SW17 ORE, UK.
4
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, 32608, USA.
5
The Vollum Institute, Oregon Health and Science University, 3181S.W. Sam Jackson Pk. Rd., Portland, OR, 97239, USA.
6
Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, 07747, Jena, Germany. Stefan.Schulz@med.uni-jena.de.

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.

PMID:
30664663
PMCID:
PMC6341117
DOI:
10.1038/s41467-018-08162-1
[Indexed for MEDLINE]
Free PMC Article

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