T394A mutation at the µ opioid receptor blocks opioid tolerance and increases vulnerability to heroin self-administration in mice

Xiao Fei Wang, Elisabeth Barbier, Yi Ting Chiu, Yi He, Jia Zhan, Guo Hua Bi, Haiying Zhang, Bo Feng, Lee Yuan Liu-Chen, Jia Bei Wang, Zheng Xiong Xi

Research output: Contribution to journalArticle

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 T394may serve as a new drug target for modulating opioid tolerance and the development of opioid abuse and addiction.

Original languageEnglish (US)
Pages (from-to)10392-10403
Number of pages12
JournalJournal of Neuroscience
Volume36
Issue number40
DOIs
StatePublished - Oct 5 2016
Externally publishedYes

Fingerprint

Self Administration
Heroin
Opioid Receptors
Opioid Analgesics
mu Opioid Receptor
Mutation
Etorphine
Analgesia
Dopamine
Phosphorylation
Posterior Horn Cells
Nucleus Accumbens
Threonine
Reward
Point Mutation
Alanine
Morphine
Single Nucleotide Polymorphism

Keywords

  • Addiction
  • Heroin
  • Mutation
  • Self-administration
  • T394A
  • µ opioid receptor

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

T394A mutation at the µ opioid receptor blocks opioid tolerance and increases vulnerability to heroin self-administration in mice. / Wang, Xiao Fei; Barbier, Elisabeth; Chiu, Yi Ting; He, Yi; Zhan, Jia; Bi, Guo Hua; Zhang, Haiying; Feng, Bo; Liu-Chen, Lee Yuan; Wang, Jia Bei; Xi, Zheng Xiong.

In: Journal of Neuroscience, Vol. 36, No. 40, 05.10.2016, p. 10392-10403.

Research output: Contribution to journalArticle

Wang, XF, Barbier, E, Chiu, YT, He, Y, Zhan, J, Bi, GH, Zhang, H, Feng, B, Liu-Chen, LY, Wang, JB & Xi, ZX 2016, 'T394A mutation at the µ opioid receptor blocks opioid tolerance and increases vulnerability to heroin self-administration in mice', Journal of Neuroscience, vol. 36, no. 40, pp. 10392-10403. https://doi.org/10.1523/JNEUROSCI.0603-16.2016
Wang, Xiao Fei ; Barbier, Elisabeth ; Chiu, Yi Ting ; He, Yi ; Zhan, Jia ; Bi, Guo Hua ; Zhang, Haiying ; Feng, Bo ; Liu-Chen, Lee Yuan ; Wang, Jia Bei ; Xi, Zheng Xiong. / T394A mutation at the µ opioid receptor blocks opioid tolerance and increases vulnerability to heroin self-administration in mice. In: Journal of Neuroscience. 2016 ; Vol. 36, No. 40. pp. 10392-10403.
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