| First Author | Zhang L | Year | 2017 |
| Journal | EMBO Mol Med | Volume | 9 |
| Issue | 11 | Pages | 1521-1536 |
| PubMed ID | 28818835 | Mgi Jnum | J:263523 |
| Mgi Id | MGI:6161999 | Doi | 10.15252/emmm.201607324 |
| Citation | Zhang L, et al. (2017) Src-dependent phosphorylation of mu-opioid receptor at Tyr(336) modulates opiate withdrawal. EMBO Mol Med 9(11):1521-1536 |
| abstractText | 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 mu-opioid receptor (MOR) at Tyr(336) by Src after prolonged opiate treatment in vitro Here, we report that the Src-mediated MOR phosphorylation at Tyr(336) is a prerequisite for opiate withdrawal in mice. We observed the recruitment of Src in the vicinity of MOR and an increase in phosphorylated Tyr(336) (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. |
