SORA

Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

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 (2019) Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects. Nature Communications, 10. p. 367. ISSN 2041-1723 https://doi.org/10.1038/s41467-018-08162-1
SGUL Authors: Bailey, Alexis

[img]
Preview
PDF Published Version
Available under License Creative Commons Attribution.

Download (1MB) | Preview

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.

Item Type: Article
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2019
Keywords: MD Multidisciplinary
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE)
Journal or Publication Title: Nature Communications
ISSN: 2041-1723
Dates:
DateEvent
21 January 2019Published
18 December 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
SFB/TR166-TPC5Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659
SCHU924/10-3Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659
DA08163National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
APP1072113National Health and Medical Research Councilhttp://dx.doi.org/10.13039/501100000925
1045964National Health and Medical Research Councilhttp://dx.doi.org/10.13039/501100000925
681120Horizon 2020UNSPECIFIED
DA038069National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
URI: http://openaccess.sgul.ac.uk/id/eprint/110559
Publisher's version: https://doi.org/10.1038/s41467-018-08162-1

Actions (login required)

Edit Item Edit Item