Src-dependent Phosphorylation of μ-opioid Receptor at Tyr Modulates Opiate Withdrawal

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2017 Aug 19

PMID 28818835

Citations 11

Authors

Lei Zhang

Cherkaouia Kibaly

Yu-Jun Wang

Chi Xu

Kyu Young Song

Patrick W McGarrah

Horace H Loh

Jing-Gen Liu

Ping-Yee Law

Affiliations

Soon will be listed here.

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 Tyr by Src after prolonged opiate treatment Here, we report that the Src-mediated MOR phosphorylation at Tyr 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 (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.

Citing Articles

AKAP150 from nucleus accumbens dopamine D1 and D2 receptor-expressing medium spiny neurons regulates morphine withdrawal.

Bai X, Zhang K, Ou C, Mu Y, Chi D, Zhang J iScience. 2023; 26(11):108227.

PMID: 37953959 PMC: 10637943. DOI: 10.1016/j.isci.2023.108227.

Microglial inflammation modulates opioid analgesic tolerance.

Pahan P, Xie J J Neurosci Res. 2023; 101(9):1383-1392.

PMID: 37186407 PMC: 11410303. DOI: 10.1002/jnr.25199.

Genetic and epigenetic studies of opioid abuse disorder - the potential for future diagnostics.

Abdulmalek S, Hardiman G Expert Rev Mol Diagn. 2023; 23(5):361-373.

PMID: 37078260 PMC: 10257799. DOI: 10.1080/14737159.2023.2190022.

Hypocretin/Orexin Interactions with Norepinephrine Contribute to the Opiate Withdrawal Syndrome.

McGregor R, Wu M, Holmes B, Lam H, Maidment N, Gera J J Neurosci. 2021; 42(2):255-263.

PMID: 34853083 PMC: 8802943. DOI: 10.1523/JNEUROSCI.1557-21.2021.

Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder.

Egervari G, Akpoyibo D, Rahman T, Fullard J, Callens J, Landry J Nat Commun. 2020; 11(1):4634.

PMID: 32929078 PMC: 7490718. DOI: 10.1038/s41467-020-18114-3.

References

Olson V, Zabetian C, Bolanos C, Edwards S, Barrot M, Eisch A . Regulation of drug reward by cAMP response element-binding protein: evidence for two functionally distinct subregions of the ventral tegmental area. J Neurosci. 2005; 25(23):5553-62. PMC: 6724971. DOI: 10.1523/JNEUROSCI.0345-05.2005. View

Boehm 2nd S, Peden L, Chang R, Harris R, Blednov Y . Deletion of the fyn-kinase gene alters behavioral sensitivity to ethanol. Alcohol Clin Exp Res. 2003; 27(7):1033-40. DOI: 10.1097/01.ALC.0000075822.80583.71. View

Stinus L, Le Moal M, Koob G . Nucleus accumbens and amygdala are possible substrates for the aversive stimulus effects of opiate withdrawal. Neuroscience. 1990; 37(3):767-73. DOI: 10.1016/0306-4522(90)90106-e. View

Zhang L, Loh H, Law P . A novel noncanonical signaling pathway for the μ-opioid receptor. Mol Pharmacol. 2013; 84(6):844-53. PMC: 3834144. DOI: 10.1124/mol.113.088278. View

Taubenfeld S, Muravieva E, Garcia-Osta A, Alberini C . Disrupting the memory of places induced by drugs of abuse weakens motivational withdrawal in a context-dependent manner. Proc Natl Acad Sci U S A. 2010; 107(27):12345-50. PMC: 2901477. DOI: 10.1073/pnas.1003152107. View

Babus L, Little E, Keenoy K, Minami S, Chen E, Song J . Decreased dendritic spine density and abnormal spine morphology in Fyn knockout mice. Brain Res. 2011; 1415:96-102. PMC: 3607202. DOI: 10.1016/j.brainres.2011.07.059. View

Zarbock A . The shady side of dasatinib. Blood. 2012; 119(21):4817-8. DOI: 10.1182/blood-2012-03-418582. View

Avidor-Reiss T, Nevo I, Levy R, Pfeuffer T, Vogel Z . Chronic opioid treatment induces adenylyl cyclase V superactivation. Involvement of Gbetagamma. J Biol Chem. 1996; 271(35):21309-15. DOI: 10.1074/jbc.271.35.21309. View

Baccarini M . Second nature: biological functions of the Raf-1 "kinase". FEBS Lett. 2005; 579(15):3271-7. DOI: 10.1016/j.febslet.2005.03.024. View

10.

Green T, Fennell M, Whittaker R, Curwen J, Jacobs V, Allen J . Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530. Mol Oncol. 2009; 3(3):248-61. PMC: 5527863. DOI: 10.1016/j.molonc.2009.01.002. View

11.

Hand T, Koob G, Stinus L, Le Moal M . Aversive properties of opiate receptor blockade: evidence for exclusively central mediation in naive and morphine-dependent rats. Brain Res. 1988; 474(2):364-8. DOI: 10.1016/0006-8993(88)90452-0. View

12.

Zhao H, Loh H, Law P . Adenylyl cyclase superactivation induced by long-term treatment with opioid agonist is dependent on receptor localized within lipid rafts and is independent of receptor internalization. Mol Pharmacol. 2006; 69(4):1421-32. DOI: 10.1124/mol.105.020024. View

13.

Delfs J, Zhu Y, Druhan J, Aston-Jones G . Noradrenaline in the ventral forebrain is critical for opiate withdrawal-induced aversion. Nature. 2000; 403(6768):430-4. DOI: 10.1038/35000212. View

14.

OBrien C, Testa T, OBrien T, Brady J, Wells B . Conditioned narcotic withdrawal in humans. Science. 1977; 195(4282):1000-2. DOI: 10.1126/science.841320. View

15.

Seth V, Upadhyaya P, Moghe V, Ahmad M . Role of calcium in morphine dependence and naloxone-precipitated withdrawal in mice. J Exp Pharmacol. 2016; 3:7-12. PMC: 4863299. DOI: 10.2147/JEP.S15240. View

16.

Hinson R, Siegel S . Nonpharmacological bases of drug tolerance and dependence. J Psychosom Res. 1982; 26(5):495-503. DOI: 10.1016/0022-3999(82)90089-7. View

17.

Hennequin L, Allen J, Breed J, Curwen J, Fennell M, Green T . N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J Med Chem. 2006; 49(22):6465-88. DOI: 10.1021/jm060434q. View

18.

Schumann G, Rujescu D, Kissling C, Soyka M, Dahmen N, Preuss U . Analysis of genetic variations of protein tyrosine kinase fyn and their association with alcohol dependence in two independent cohorts. Biol Psychiatry. 2003; 54(12):1422-6. DOI: 10.1016/s0006-3223(03)00635-8. View

19.

Edwards S, Graham D, Whisler K, Self D . Phosphorylation of GluR1, ERK, and CREB during spontaneous withdrawal from chronic heroin self-administration. Synapse. 2008; 63(3):224-35. PMC: 2628418. DOI: 10.1002/syn.20601. View

20.

Kibaly C, Lin H, Loh H, Law P . Spinal or supraspinal phosphorylation deficiency at the MOR C-terminus does not affect morphine tolerance in vivo. Pharmacol Res. 2017; 119:153-168. PMC: 5392433. DOI: 10.1016/j.phrs.2017.01.033. View