Morphine-induced μ-opioid receptor rapid desensitization is independent of receptor phosphorylation and β-arrestins

Ji Chu, Hui Zheng, Horace H Loh, Ping-Yee Law

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47 Scopus citations

Abstract

Receptor desensitization involving receptor phosphorylation and subsequent βArrestin (βArr) recruitment has been implicated in the tolerance development mediated by μ-opioid receptor (OPRM1). However, the roles of receptor phosphorylation and βArr on morphine-induced OPRM1 desensitization remain to be demonstrated. Using OPRM1-induced intracellular Ca2+ ([Ca2+]i)release to monitor receptor activation, as predicted, [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO), induced OPRM1 desensitization in a receptor phosphorylation- and βArr-dependent manner. The DAMGO-induced OPRM1 desensitization was attenuated significantly when phosphorylation deficient OPRM1 mutants or Mouse Embryonic Fibroblast (MEF) cells from βArr1 and 2 knockout mice were used in the studies. Specifically, DAMGO-induced desensitization was blunted in HEK293 cells expressing the OPRM1S375A mutant and was eliminated in MEF cells isolated from βArr2 knockout mice expressing the wild type OPRM1. However, although morphine also could induce a rapid desensitization on [Ca2+]i release to a greater extent than that of DAMGO and could induce the phosphorylation of Ser375 residue, morphine-induced desensitization was not influenced by mutating the phosphorylation sites or in MEF cells lacking βArr1 and 2. Hence, morphine could induce OPRM1 desensitization via pathway independent of βArr, thus suggesting the in vivo tolerance development to morphine can occur in the absence of βArr.

Original languageEnglish (US)
Pages (from-to)1616-1624
Number of pages9
JournalCellular Signalling
Volume20
Issue number9
DOIs
StatePublished - Sep 2008

Bibliographical note

Funding Information:
This research was supported in parts by National Institutes of Healthy grants DA007339, DA016674, DA000564 and DA011806. H.H.L. and P.Y.L. are recipients of K05-DA70544 and K05-DA00513, respectively. Dr. Robert Lefkowitz (Duke University, NC) generously provided the wild type, βArr2 −/− and βArr1/2 −/− Mouse Embryonic Fibroblasts cells used in current studies. Dr. Mario Ascoli (University of Iowa, Iowa City) generously provided the βArr2FLAG construct.

Keywords

  • Desensitization
  • Morphine
  • Phosphorylation
  • [D-Ala, N-Me-Phe, Gly-ol]-enkephalin (DAMGO)
  • βArrestin(βArr)
  • μ-opioid receptor (OPRM1)

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