Alcohol-aggravated episodic pain in humans with SCN11A mutation and ALDH2 polymorphism.
Alcohol-aggravated episodic pain in humans with SCN11A mutation and ALDH2 polymorphism.
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DOI：
10.1097/j.pain.0000000000001853
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发表时间：
2020-02
期刊：
影响因子：
7.4
通讯作者：
Luyao Yang;Lulu Li;Haiyan Tang;Tingbin Ma;Yulei Li;Xianwei Zhang;Xiaoliu Shi;Jing Yu Liu
中科院分区：
文献类型：
--
作者：
Luyao Yang;Lulu Li;Haiyan Tang;Tingbin Ma;Yulei Li;Xianwei Zhang;Xiaoliu Shi;Jing Yu Liu
SCN11A 编码的 Nav1.9 突变与阵发性疼痛、小纤维神经病和先天性疼痛不敏感有关。在这项研究中，我们收集并描述了一个患有阵发性疼痛的中国家庭。鉴定出 SCN11A 突变 (c.664C>A/p.Arg222Ser) 并与阵发性疼痛表型共分离。此外，我们发现酒精摄入会引发剧烈疼痛，并在三名阵发性疼痛患者中检测到 ALDH2 多态性 (c.1510G>A/p.Glu504Lys)。酒精加重的疼痛症状和这种 ALDH2 多态性也在我们之前报道的具有 Nav1.9 突变的阵发性疼痛患者（p.Ala808Gly，HBBJ 家族患者 III-2）中得到再次证实。为了评估 Nav1.9 突变和新触发因素的致病性，我们将突变 (p.Ala796Gly) 引入小鼠体内（人类的直系同源突变为 p.Ala808Gly）。这种改变使通道激活超极化，增加了非失活通道的残余电流，并诱导 Scn11a 小鼠的背根神经节 (DRG) 神经元过度兴奋。 Scn11a 小鼠表现出对机械、热和冷刺激的敏感性增加，以及对乙醛和福尔马林的超敏性，这可以解释患者因酒精摄入引起的疼痛表型。此外，乙醛增加了Scn11a小鼠DRG神经元的突变mNav1.9通道电流和兴奋性。帕瑞昔布（一种抗炎药物）可缓解未接受炎症刺激的 Scn11a 小鼠的热超敏反应，并显着降低 Scn11a 小鼠 DRG 神经元的过度兴奋。这些结果表明，Scn11a 小鼠重现了患者的许多临床特征，并表明 Nav1.9 通道对炎性疼痛状态有显着影响。
Mutations in Nav1.9 encoded by SCN11A have 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. The SCN11A mutation (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 the ALDH2 polymorphism (c.1510G>A/p.Glu504Lys) in three patients with episodic pain. The alcohol-aggravated pain symptom and this ALDH2 polymorphism were also reconfirmed in our previously reported episodic pain patient with the Nav1.9 mutation (p.Ala808Gly, patient III-2 in HBBJ family). To assess the pathogenicity of the Nav1.9 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 non-inactivating channels, and induced hyperexcitability of dorsal root ganglion (DRG) neurons in Scn11a mice. The Scn11a 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 mNav1.9 channel current and excitability of Scn11a mouse DRG neurons. Parecoxib (an anti-inflammatory medication) relieved the heat hypersensitivity in Scn11a mice not receiving inflammatory stimuli and significantly decreased the hyperexcitability of DRG neurons in Scn11a mice. These results indicated that Scn11a mice recapitulated many clinical features of patients and suggested that Nav1.9 channel contributes significantly to the inflammatory pain state.