Publication in detail

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.

Kliewer, A; Schmiedel, F; Sianati, S; Bailey, A; Bateman, JT; Levitt, ES; Williams, JT; Christie, MJ; Schulz, S

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

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.

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