μ-Opioid receptor desensitization: Is morphine different?

Mark Connor*, Peregrine B. Osborne, MacDonald J. Christie

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

86 Citations (Scopus)

Abstract

Opioid tolerance and dependence are important phenomena. The contribution of acute μ-opioid receptor regulatory mechanisms to the development of analgesic tolerance or physical dependence are unknown, and even the mechanisms underlying relatively rapid receptor desensitization in single cells are unresolved. To a large degree, the uncertainty surrounding the mechanisms and consequences of short-term regulation of μ-opioid receptors in single cells arises from the limitations in the experimental design in many of the studies that have investigated these events. Receptor overexpression and use of assays in which regulatory mechanisms are likely to blunt control determinations have led to measurements of opioid receptor activity that are likely to be insensitive to receptor uncoupling. Together with uncertainties concerning molecular details of μ-opioid receptor interactions with potential regulatory molecules such as G protein-coupled receptor kinases and arresting, we are left with an incomplete picture crudely copied from the well-worked-out regulatory schema for β 2-adrenoceptors. As a consequence, suggestions that clinically relevant μ-opioid receptor agonists may have different propensities to produce tolerance and dependence that arise from their differential recruitment of regulatory mechanisms are premature, and have not yet been appropriately assessed, nor explained in the context of a thoroughly established regulatory scheme. In this commentary, we outline the experimental limitations that have given rise to conflicting ideas about how μ-opioid receptors are regulated, and identify the issues we feel still need to be addressed before we can understand why morphine promotes receptor trafficking differently to other opioids.

Original languageEnglish
Pages (from-to)685-696
Number of pages12
JournalBritish Journal of Pharmacology
Volume143
Issue number6
DOIs
Publication statusPublished - Nov 2004
Externally publishedYes

Keywords

  • DAMGO
  • Efficacy
  • Etorphine
  • Internalization
  • Opioid dependence
  • Opioid tolerance
  • Phosphorylation

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