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.
Bibliographical noteFunding 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).
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- Src-mediated phosphorylation of MOR at Tyr
- lentivirus injection
- locus coeruleus
- naloxone-precipitated opiate withdrawal
- opiate addiction