Src-dependent phosphorylation of μ-opioid receptor at Tyr 336 modulates opiate withdrawal

Lei Zhang, Cherkaouia Kibaly, Yu Jun Wang, Chi Xu, Kyu Young Song, Patrick W. McGarrah, Horace H. Loh, Jing Gen Liu, Ping Yee Law

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19 Scopus citations


Opiate withdrawal/negative reinforcement has been implicated as one of the mechanisms for the progression from impulsive to compulsive drug use. Increase in the intracellular cAMP level and protein kinase A (PKA) activities within the neurocircuitry of addiction has been a leading hypothesis for opiate addiction. This increase requires the phosphorylation of μ-opioid receptor (MOR) at Tyr336 by Src after prolonged opiate treatment in vitro. Here, we report that the Src-mediated MOR phosphorylation at Tyr336 is a prerequisite for opiate withdrawal in mice. We observed the recruitment of Src in the vicinity of MOR and an increase in phosphorylated Tyr336 (pY336) levels during naloxone-precipitated withdrawal. The intracerebroventricular or stereotaxic injection of a Src inhibitor (AZD0530), or Src shRNA viruses attenuated pY336 levels, and several somatic withdrawal signs. This was also observed in Fyn−/− mice. The stereotaxic injection of wild-type MOR, but not mutant (Y336F) MOR, lentiviruses into the locus coeruleus of MOR−/− mice restored somatic withdrawal jumping. Regulating pY336 levels during withdrawal might be a future target for drug development to prevent opiate addictive behaviors.

Original languageEnglish (US)
Pages (from-to)1521-1536
Number of pages16
JournalEMBO Molecular Medicine
Issue number11
StatePublished - Nov 2017

Bibliographical note

Publisher Copyright:
© 2017 The Authors. Published under the terms of the CC BY 4.0 license


  • Src-mediated phosphorylation of MOR at Tyr
  • lentivirus injection
  • locus coeruleus
  • naloxone-precipitated opiate withdrawal
  • opiate addiction


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