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Review ArticleReview Article

Regulation of µ-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance

John T. Williams, Susan L. Ingram, Graeme Henderson, Charles Chavkin, Mark von Zastrow, Stefan Schulz, Thomas Koch, Christopher J. Evans and MacDonald J. Christie
Annette C. Dolphin, ASSOCIATE EDITOR
Pharmacological Reviews January 2013, 65 (1) 223-254; DOI: https://doi.org/10.1124/pr.112.005942
John T. Williams
Vollum Institute, Oregon Health Sciences University, Portland, Oregon (J.T.W.); Department of Neurologic Surgery, Oregon Health Sciences University, Portland, Oregon (S.L.I.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (G.H.); Department of Pharmacology, University of Washington, Seattle, Washington (C.C.); Psychiatry and Pharmacology, University of California at San Francisco, San Francisco, California (M.v.Z.); Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (S.S.); Institute of Pharmacology and Toxicology, University of Magdeburg, Magdeburg, Germany (T.K.); Hatos Center of Neuropharmacology, University of California at Los Angeles (C.J.E.); and Discipline of Pharmacology, University of Sydney, Sydney, New South Wales, Australia (M.J.C.)
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Susan L. Ingram
Vollum Institute, Oregon Health Sciences University, Portland, Oregon (J.T.W.); Department of Neurologic Surgery, Oregon Health Sciences University, Portland, Oregon (S.L.I.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (G.H.); Department of Pharmacology, University of Washington, Seattle, Washington (C.C.); Psychiatry and Pharmacology, University of California at San Francisco, San Francisco, California (M.v.Z.); Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (S.S.); Institute of Pharmacology and Toxicology, University of Magdeburg, Magdeburg, Germany (T.K.); Hatos Center of Neuropharmacology, University of California at Los Angeles (C.J.E.); and Discipline of Pharmacology, University of Sydney, Sydney, New South Wales, Australia (M.J.C.)
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Graeme Henderson
Vollum Institute, Oregon Health Sciences University, Portland, Oregon (J.T.W.); Department of Neurologic Surgery, Oregon Health Sciences University, Portland, Oregon (S.L.I.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (G.H.); Department of Pharmacology, University of Washington, Seattle, Washington (C.C.); Psychiatry and Pharmacology, University of California at San Francisco, San Francisco, California (M.v.Z.); Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (S.S.); Institute of Pharmacology and Toxicology, University of Magdeburg, Magdeburg, Germany (T.K.); Hatos Center of Neuropharmacology, University of California at Los Angeles (C.J.E.); and Discipline of Pharmacology, University of Sydney, Sydney, New South Wales, Australia (M.J.C.)
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Charles Chavkin
Vollum Institute, Oregon Health Sciences University, Portland, Oregon (J.T.W.); Department of Neurologic Surgery, Oregon Health Sciences University, Portland, Oregon (S.L.I.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (G.H.); Department of Pharmacology, University of Washington, Seattle, Washington (C.C.); Psychiatry and Pharmacology, University of California at San Francisco, San Francisco, California (M.v.Z.); Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (S.S.); Institute of Pharmacology and Toxicology, University of Magdeburg, Magdeburg, Germany (T.K.); Hatos Center of Neuropharmacology, University of California at Los Angeles (C.J.E.); and Discipline of Pharmacology, University of Sydney, Sydney, New South Wales, Australia (M.J.C.)
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Mark von Zastrow
Vollum Institute, Oregon Health Sciences University, Portland, Oregon (J.T.W.); Department of Neurologic Surgery, Oregon Health Sciences University, Portland, Oregon (S.L.I.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (G.H.); Department of Pharmacology, University of Washington, Seattle, Washington (C.C.); Psychiatry and Pharmacology, University of California at San Francisco, San Francisco, California (M.v.Z.); Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (S.S.); Institute of Pharmacology and Toxicology, University of Magdeburg, Magdeburg, Germany (T.K.); Hatos Center of Neuropharmacology, University of California at Los Angeles (C.J.E.); and Discipline of Pharmacology, University of Sydney, Sydney, New South Wales, Australia (M.J.C.)
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Stefan Schulz
Vollum Institute, Oregon Health Sciences University, Portland, Oregon (J.T.W.); Department of Neurologic Surgery, Oregon Health Sciences University, Portland, Oregon (S.L.I.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (G.H.); Department of Pharmacology, University of Washington, Seattle, Washington (C.C.); Psychiatry and Pharmacology, University of California at San Francisco, San Francisco, California (M.v.Z.); Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (S.S.); Institute of Pharmacology and Toxicology, University of Magdeburg, Magdeburg, Germany (T.K.); Hatos Center of Neuropharmacology, University of California at Los Angeles (C.J.E.); and Discipline of Pharmacology, University of Sydney, Sydney, New South Wales, Australia (M.J.C.)
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Thomas Koch
Vollum Institute, Oregon Health Sciences University, Portland, Oregon (J.T.W.); Department of Neurologic Surgery, Oregon Health Sciences University, Portland, Oregon (S.L.I.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (G.H.); Department of Pharmacology, University of Washington, Seattle, Washington (C.C.); Psychiatry and Pharmacology, University of California at San Francisco, San Francisco, California (M.v.Z.); Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (S.S.); Institute of Pharmacology and Toxicology, University of Magdeburg, Magdeburg, Germany (T.K.); Hatos Center of Neuropharmacology, University of California at Los Angeles (C.J.E.); and Discipline of Pharmacology, University of Sydney, Sydney, New South Wales, Australia (M.J.C.)
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Christopher J. Evans
Vollum Institute, Oregon Health Sciences University, Portland, Oregon (J.T.W.); Department of Neurologic Surgery, Oregon Health Sciences University, Portland, Oregon (S.L.I.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (G.H.); Department of Pharmacology, University of Washington, Seattle, Washington (C.C.); Psychiatry and Pharmacology, University of California at San Francisco, San Francisco, California (M.v.Z.); Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (S.S.); Institute of Pharmacology and Toxicology, University of Magdeburg, Magdeburg, Germany (T.K.); Hatos Center of Neuropharmacology, University of California at Los Angeles (C.J.E.); and Discipline of Pharmacology, University of Sydney, Sydney, New South Wales, Australia (M.J.C.)
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MacDonald J. Christie
Vollum Institute, Oregon Health Sciences University, Portland, Oregon (J.T.W.); Department of Neurologic Surgery, Oregon Health Sciences University, Portland, Oregon (S.L.I.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (G.H.); Department of Pharmacology, University of Washington, Seattle, Washington (C.C.); Psychiatry and Pharmacology, University of California at San Francisco, San Francisco, California (M.v.Z.); Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (S.S.); Institute of Pharmacology and Toxicology, University of Magdeburg, Magdeburg, Germany (T.K.); Hatos Center of Neuropharmacology, University of California at Los Angeles (C.J.E.); and Discipline of Pharmacology, University of Sydney, Sydney, New South Wales, Australia (M.J.C.)
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Annette C. Dolphin
Vollum Institute, Oregon Health Sciences University, Portland, Oregon (J.T.W.); Department of Neurologic Surgery, Oregon Health Sciences University, Portland, Oregon (S.L.I.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (G.H.); Department of Pharmacology, University of Washington, Seattle, Washington (C.C.); Psychiatry and Pharmacology, University of California at San Francisco, San Francisco, California (M.v.Z.); Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany (S.S.); Institute of Pharmacology and Toxicology, University of Magdeburg, Magdeburg, Germany (T.K.); Hatos Center of Neuropharmacology, University of California at Los Angeles (C.J.E.); and Discipline of Pharmacology, University of Sydney, Sydney, New South Wales, Australia (M.J.C.)
Roles: ASSOCIATE EDITOR
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Abstract

Morphine and related µ-opioid receptor (MOR) agonists remain among the most effective drugs known for acute relief of severe pain. A major problem in treating painful conditions is that tolerance limits the long-term utility of opioid agonists. Considerable effort has been expended on developing an understanding of the molecular and cellular processes that underlie acute MOR signaling, short-term receptor regulation, and the progression of events that lead to tolerance for different MOR agonists. Although great progress has been made in the past decade, many points of contention and controversy cloud the realization of this progress. This review attempts to clarify some confusion by clearly defining terms, such as desensitization and tolerance, and addressing optimal pharmacological analyses for discerning relative importance of these cellular mechanisms. Cellular and molecular mechanisms regulating MOR function by phosphorylation relative to receptor desensitization and endocytosis are comprehensively reviewed, with an emphasis on agonist-biased regulation and areas where knowledge is lacking or controversial. The implications of these mechanisms for understanding the substantial contribution of MOR signaling to opioid tolerance are then considered in detail. While some functional MOR regulatory mechanisms contributing to tolerance are clearly understood, there are large gaps in understanding the molecular processes responsible for loss of MOR function after chronic exposure to opioids. Further elucidation of the cellular mechanisms that are regulated by opioids will be necessary for the successful development of MOR-based approaches to new pain therapeutics that limit the development of tolerance.

Footnotes

  • This work was supported by grants from the National Institutes of Health National Institute on Drug Abuse [Grants DA01863 (to J.T.W.), DA027625 (to S.I.), DA020836 (to G.H.), K0-5DA20570 (to C.C.), DA012864 (to Mv.Z.), and DA005010 (C.E.)]; the Deutsche Forschungsgemeinschaft [SCH924/11-2, S.S.], the Deutsche Forschungsgemeinschaft [GRK 1167/-1], and the Federal State of Saxony-Anhalt and the “European Regional Development Fund” [Grant ERDF 2007-2013] (to T.K.); and the National Health and Medical Research Council of Australia [Grants 1011979 and 511914] (to M.J.C.).

  • dx.doi.org/10.1124/pr.112.005942.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 65 (1)
Pharmacological Reviews
Vol. 65, Issue 1
1 Jan 2013
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Review ArticleReview Article

Regulation of μ-Opioid Receptors

John T. Williams, Susan L. Ingram, Graeme Henderson, Charles Chavkin, Mark von Zastrow, Stefan Schulz, Thomas Koch, Christopher J. Evans and MacDonald J. Christie
Pharmacological Reviews January 1, 2013, 65 (1) 223-254; DOI: https://doi.org/10.1124/pr.112.005942

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Review ArticleReview Article

Regulation of μ-Opioid Receptors

John T. Williams, Susan L. Ingram, Graeme Henderson, Charles Chavkin, Mark von Zastrow, Stefan Schulz, Thomas Koch, Christopher J. Evans and MacDonald J. Christie
Pharmacological Reviews January 1, 2013, 65 (1) 223-254; DOI: https://doi.org/10.1124/pr.112.005942
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  • Article
    • Abstract
    • I. Introduction
    • II. Definition of Terms
    • III. Structure and Function of μ-Opioid Receptors
    • IV. μ-Opioid Receptor Regulation
    • V. Phosphorylation and μ-Opioid Receptor Regulation
    • VI. Internalization, Phosphatase Activity, and Recovery from Desensitization
    • VII. Cellular Adaptations Induced during Morphine Tolerance
    • VIII. Implications and Outstanding Questions
    • IX. Concluding Remarks
    • Acknowledgments
    • Authorship Contibutions
    • Footnotes
    • Abbreviations
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