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

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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
Volume9
Issue number11
DOIs
StatePublished - Nov 2017

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health DA031442, USA (PYL, LZ, CK, CX, KYS, PWM, HHL); from the Ministry of Science and Technology of China 2013CB835100 and 2015CB553502 (JGL); from the National Natural Science Foundation of China 81130087, 81671322 (JGL), and 81401107 (YJW); from the President’s International Fellowship Initiative Program of the Chinese Academy of Sciences 2011T2S29 (PYL); and from the Youth Innovation Promotion Association of the Chinese Academy of Sciences 2017334 (YJW).

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

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Keywords

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

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