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

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          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.

          Abstract

          Tolerance and other side effects are important limitations to the use of opioids as analgesics. In this study, the authors generated mice lacking phosphorylation sites on the µ-opioid receptor to assess their contribution to the analgesic, tolerance and side effect profile of opioid analgesics.

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          Most cited references35

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          Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence.

          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 responsiveness. 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 beta-arrestins. Using a knockout mouse lacking beta-arrestin-2 (beta arr2-/-), we have assessed the contribution of desensitization of the mu-opioid receptor to the development of morphine antinociceptive tolerance and the subsequent onset of physical dependence. Here we show that in mice lacking beta-arrestin-2, desensitization of the mu-opioid receptor does not occur after chronic morphine treatment, and that these animals fail to develop antinociceptive tolerance. However, the deletion of beta-arrestin-2 does not prevent the chronic morphine-induced up-regulation of adenylyl cyclase activity, a cellular marker of dependence, and the mutant mice still become physically dependent on the drug.
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            Functional selectivity and biased receptor signaling.

            With the emergence of information describing functional selectivity and biased agonists and antagonists has come a lack of confidence in "one size fits all" assays for detection of agonism. Seven-transmembrane receptors are pleiotropic with respect to the signaling protein to which they couple in a cell, and many conformations of the receptor can be formed; this leads to systems where ligands can stabilize unique conformations that go on to selectively activate signaling pathways. Thus, such "biased" ligands can produce cell-specific agonism that may require targeted assays to detect and quantify. It also predicts that ligands can have many different efficacies for the many behaviors that the receptor can exhibit (referred to as "pluridimensional efficacy"), leading to a breakdown in the common classifications of agonist and antagonist. This all poses unique challenges to the pharmacologic nomenclature of drugs, the detection and optimization of new drugs, and the association of phenotypic clinical profiles with pharmacological properties of drugs.
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              Neuroscience of addiction.

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                Author and article information

                Contributors
                Stefan.Schulz@med.uni-jena.de
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                21 January 2019
                21 January 2019
                2019
                : 10
                : 367
                Affiliations
                [1 ]Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, 07747 Jena, Germany
                [2 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Discipline of Pharmacology, School of Medical Sciences, , University of Sydney, ; NSW, 2006 Australia
                [3 ]ISNI 0000 0000 8546 682X, GRID grid.264200.2, Institute of Medical and Biomedical Education, , St George’s University of London, ; London, SW17 ORE UK
                [4 ]ISNI 0000 0004 1936 8091, GRID grid.15276.37, Department of Pharmacology and Therapeutics, , University of Florida, ; Gainesville, FL 32608 USA
                [5 ]ISNI 0000 0000 9758 5690, GRID grid.5288.7, The Vollum Institute, , Oregon Health and Science University, ; 3181S.W. Sam Jackson Pk. Rd., Portland, OR 97239 USA
                Author information
                http://orcid.org/0000-0002-0622-609X
                http://orcid.org/0000-0002-5997-8885
                Article
                8162
                10.1038/s41467-018-08162-1
                6341117
                30664663
                efbb63de-b491-4ff7-b0bb-71090d46f7f1
                © The Author(s) 2019

                Open Access 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/.

                History
                : 24 May 2018
                : 18 December 2018
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