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Morphine-induced mu-opioid receptor rapid desensitization is independent of receptor phosphorylation and

Ji Chu1, Hui Zheng, Horace H Loh

  • 1Department of Pharmacology, Medical School, University of Minnesota, Minneapolis, MN 55455-0217, USA. chux0086@umn.edu

Cellular Signalling
|June 19, 2008
PubMed

Insights

Morphine tolerance may develop independently of beta-arrestin (betaArr) pathways. While DAMGO-induced mu-opioid receptor (OPRM1) desensitization requires betaArr, morphine desensitization occurs via a betaArr-independent mechanism.

Area of Science:

  • Pharmacology
  • Neuroscience
  • Molecular Biology

Background:

  • Opioid tolerance is linked to mu-opioid receptor (OPRM1) desensitization, involving phosphorylation and beta-arrestin (betaArr) recruitment.
  • The precise roles of OPRM1 phosphorylation and betaArr in morphine-induced desensitization are not fully understood.

Purpose of the Study:

  • To investigate the involvement of OPRM1 phosphorylation and betaArr in DAMGO- and morphine-induced receptor desensitization.
  • To elucidate the mechanisms underlying OPRM1 desensitization and its potential contribution to opioid tolerance.

Main Methods:

  • Utilized intracellular calcium ([Ca(2+)](i)) release as a readout for OPRM1 activation and desensitization.
  • Employed OPRM1 phosphorylation-deficient mutants (e.g., OPRM1S375A) and betaArr1/2 knockout mouse embryonic fibroblast (MEF) cells.
  • Compared desensitization induced by DAMGO and morphine in various cell systems.

Main Results:

  • DAMGO-induced OPRM1 desensitization was dependent on both OPRM1 phosphorylation and betaArr (betaArr1 and betaArr2).
  • Morphine induced rapid OPRM1 desensitization and Ser(375) phosphorylation, but this process was independent of OPRM1 phosphorylation sites and betaArr.
  • Morphine-induced OPRM1 desensitization occurred via a betaArr-independent pathway.

Conclusions:

  • Morphine can desensitize the mu-opioid receptor (OPRM1) through a mechanism that does not require beta-arrestin (betaArr).
  • This suggests that in vivo tolerance to morphine can develop even in the absence of betaArr.
  • Highlights distinct signaling pathways for different opioid agonists in OPRM1 desensitization.

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