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 language | English (US) |
|---|---|
| Pages (from-to) | 10392-10403 |
| Number of pages | 12 |
| Journal | Journal of Neuroscience |
| Volume | 36 |
| Issue number | 40 |
| DOIs | |
| State | Published - Oct 5 2016 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - T394A mutation at the µ opioid receptor blocks opioid tolerance and increases vulnerability to heroin self-administration in mice
AU - Wang, Xiao Fei
AU - Barbier, Elisabeth
AU - Chiu, Yi Ting
AU - He, Yi
AU - Zhan, Jia
AU - Bi, Guo Hua
AU - Zhang, Haiying
AU - Feng, Bo
AU - Liu-Chen, Lee Yuan
AU - Wang, Jia Bei
AU - Xi, Zheng Xiong
PY - 2016/10/5
Y1 - 2016/10/5
N2 - 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.
AB - 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.
KW - Addiction
KW - Heroin
KW - Mutation
KW - Self-administration
KW - T394A
KW - µ opioid receptor
UR - http://www.scopus.com/inward/record.url?scp=84990831665&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84990831665&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0603-16.2016
DO - 10.1523/JNEUROSCI.0603-16.2016
M3 - Article
C2 - 27707973
AN - SCOPUS:84990831665
VL - 36
SP - 10392
EP - 10403
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 40
ER -