Alcohol-aggravated episodic pain in humans with SCN11A mutation and ALDH2 polymorphism

被引:10
|
作者
Yang, Luyao [1 ]
Li, Lulu [1 ]
Tang, Haiyan [2 ]
Ma, Tingbin [1 ]
Li, Yulei [1 ]
Zhang, Xianwei [3 ]
Shi, Xiaoliu [4 ]
Liu, Jing Yu [1 ,5 ]
机构
[1] Huazhong Univ Sci & Technol HUST, Coll Life Sci & Technol, Key Lab Mol Biophys, Minist Educ, Wuhan, Peoples R China
[2] Cent South Univ, Ctr Med Genet, Sch Life Sci, Changsha, Peoples R China
[3] HUST, Dept Anesthesiol, Tongji Hosp, Wuhan, Peoples R China
[4] Cent South Univ, Xiangya Hosp 2, Dept Med Genet, Changsha, Peoples R China
[5] Chinese Acad Sci, CAS Ctr Excellence Brain Sci & Intelligence Techn, State Key Lab Neurosci, Inst Neurosci,Shanghai Inst Biol Sci, Shanghai, Peoples R China
基金
中国国家自然科学基金;
关键词
Na(v)1; 9; Alcohol-aggravated episodic pain; ALDH2; Parecoxib; Scn11aknock-in mice; SODIUM-CHANNEL NA(V)1.9; OF-FUNCTION MUTATIONS; ALDEHYDE DEHYDROGENASE; NAV1.9; ACETALDEHYDE; INFLAMMATION; GENOTYPES; VARIANTS;
D O I
10.1097/j.pain.0000000000001853
中图分类号
R614 [麻醉学];
学科分类号
100217 ;
摘要
Mutations in Na(v)1.9 encoded bySCN11Ahave been associated with episodic pain, small-fiber neuropathy, and congenital insensitivity to pain. In this study, we collected and characterized one Chinese family with episodic pain. TheSCN11Amutation (c.664C>A/p.Arg222Ser) was identified and cosegregated with the episodic pain phenotype. In addition, we found that alcohol intake triggered intense pain attacks and detected theALDH2polymorphism (c.1510G>A/p.Glu504Lys) in 3 patients with episodic pain. The alcohol-aggravated pain symptom and thisALDH2polymorphism were also reconfirmed in our previously reported episodic pain patient with the Na(v)1.9 mutation (p.Ala808Gly, patient III-2 in HBBJ family). To assess the pathogenicity of the Na(v)1.9 mutation and the new trigger, we introduced a mutation (p.Ala796Gly) into the mouse (orthologous mutation in human is p.Ala808Gly). The alteration hyperpolarized channel activation, increased the residual current through noninactivating channels, and induced hyperexcitability of dorsal root ganglion (DRG) neurons inScn11a(A796G/A796G)mice. TheScn11a(A796G/A796G)mice showed increased sensitivity to mechanical, heat, and cold stimuli, and hypersensitivity to acetaldehyde and formalin, which could account for the alcohol intake-induced pain phenotype in patients. Moreover, acetaldehyde increased the mutant mNa(v)1.9 channel current and excitability ofScn11a(A796G/A796G)mouse DRG neurons. Parecoxib (an anti-inflammatory medication) relieved the heat hypersensitivity inScn11a(A796G/A796G)mice not receiving inflammatory stimuli and significantly decreased the hyperexcitability of DRG neurons inScn11a(A796G/A796G)mice. These results indicated thatScn11a(A796G/A796G)mice recapitulated many clinical features of patients and suggested that Na(v)1.9 channel contributes significantly to the inflammatory pain state.
引用
收藏
页码:1470 / 1482
页数:13
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