title: T394A Mutation at the μ Opioid Receptor Blocks Opioid Tolerance and Increases Vulnerability to Heroin Self-Administration in Mice.
abstract: The etiology and pathophysiology underlying opioid tolerance and dependence are still unknown. Because mu opioid receptor (MOR) plays an essential role in opioid action, many vulnerability-related studies have focused on single nucleotide polymorphisms of MOR, particularly on A118G. In this study, we found that a single-point mutation at the MOR T394 phosphorylation site could be another important susceptive factor in the development of opioid tolerance and dependence in mice. T394A mutation, in which a threonine at 394 was replaced by an alanine, did not alter agonist binding to MOR and opioid analgesia, but resulted in loss of etorphine-induced MOR internalization in spinal dorsal horn neurons and opioid analgesic tolerance induced by either morphine or etorphine. In addition, this mutation also caused an increase in intravenous heroin self-administration and in nucleus accumbens dopamine response to heroin. These findings suggest that T394 phosphorylation following MOR activation causes MOR internalization and desensitization, which subsequently contributes to the development of tolerance in both opioid analgesia and opioid reward. Accordingly, T394A mutation blocks opioid tolerance and leads to an increase in brain dopamine response to opioids and in opioid-taking behavior. Thus, the T394 may serve as a new drug target for modulating opioid tolerance and the development of opioid abuse and addiction.
  
  
  
  The mechanisms underlying opioid tolerance and susceptibility to opioid addiction remain unclear. The present studies demonstrate that a single-point mutation at the T394 phosphorylation site in the C-terminal of mu opioid receptor (MOR) results in loss of opioid tolerance and enhanced vulnerability to heroin self-administration. These findings suggest that modulation of the MOR-T394 phosphorylation or dephosphorylation status may have therapeutic potential in management of pain, opioid tolerance, and opioid abuse and addiction. Accordingly, MOR-T394 mutation or polymorphisms could be a risk factor in developing opioid abuse and addiction and therefore be used as a new biomarker in prediction and prevention of opioid abuse and addiction.
authors.affiliation: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Xiao-Fei
authors.identifier: 0000-0001-7901-5034
authors.initials: XF
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Barbier
authors.affiliation: Department of Pharmacology, School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, and.
authors.forename: Yi-Ting
authors.identifier: 0000-0001-7257-7755
authors.initials: YT
authors.lastname: Chiu
authors.affiliation: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224.
authors.forename: Yi
authors.initials: Y
authors.lastname: He
authors.affiliation: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhan
authors.affiliation: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Bi
authors.affiliation: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224.
authors.forename: Hai-Ying
authors.identifier: 0000-0003-0593-5940
authors.initials: HY
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201.
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.affiliation: Department of Pharmacology, School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, and.
authors.forename: Lee-Yuan
authors.initials: LY
authors.lastname: Liu-Chen
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, zxi@mail.nih.gov jwang@rx.umaryland.edu.
authors.forename: Jia Bei
authors.initials: JB
authors.lastname: Wang
authors.affiliation: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224, zxi@mail.nih.gov jwang@rx.umaryland.edu.
authors.forename: Zheng-Xiong
authors.identifier: 0000-0001-6482-8104
authors.initials: ZX
authors.lastname: Xi
mesh_terms: D000698:Analgesia; D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004361:Drug Tolerance / Q000235:genetics*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism; D005048:Etorphine / Q000494:pharmacology; D006556:Heroin Dependence / Q000235:genetics* / Q000523:psychology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation; D010147:Pain Measurement / Q000187:drug effects; D010766:Phosphorylation; D017354:Point Mutation / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000235:genetics*; D012201:Reward; D012646:Self Administration
chemical_list: D000701:Analgesics, Opioid; C404943:Oprm protein, mouse; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005048:Etorphine; D009020:Morphine
keywords: T394A; addiction; heroin; mutation; self-administration; μ opioid receptor