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Abstract：
Mutations within the SCN11A gene which encodes the voltage-gated sodium channel NaV1.9 mainly expressed in small fiber sensory neurons have been associated with neuropathic disorders; however, suitable medications have not been fully investigated. To develop drug therapies against NaV1.9-related neuropathic pain, we aimed to establish a novel model using mice carrying the Scn11a p.R222S mutation initially identified in patients with familial episodic limb pain that is characterized by paroxysmal pain induced by fatigue or bad weather conditions. We investigated the influence of cold exposure (4 °C, overnight) on the behavioral and biochemical phenotypes of Scn11a p.R222S mutant (R222S) and wild type C57BL/6N (WT) mice. We also tested the effects of acetaminophen (125, 250 mg/kg, perorally, p.o.) and traditional Japanese medicine, goshajinkigan (0.5 or 1.0 g/kg, p.o.), which are analgesic drugs prescribed to patients with neuropathic pain, in this model of cold-induced mechanical allodynia in R222S mice.Cold-exposed R222S mice exhibited enhanced mechanical allodynia and thermal hypersensitivity compared with WT mice. The decrease of the mechanical withdrawal threshold in R222S mice was reversible 24 h after housing at room temperature. There was no significant change in the levels of interleukin-1β, interleukin-6, tumor necrosis factor-α, or interferon-γ in the plasma or spinal cords of WT and R222S mice after cold exposure. Both acetaminophen (250 mg/kg) and goshajinkigan (1.0 g/kg) significantly attenuated mechanical allodynia in R222S mice. The model of cold-induced mechanical allodynia in mice with the Scn11a p.R222S mutation is novel and useful for evaluating analgesic drugs for intractable neuropathies related to NaV1.9.
摘要：
编码主要在小纤维感觉神经元中表达的电压门控钠通道NaV1.9的SCN11A基因内的突变与神经病变有关；然而，合适的药物尚未得到充分研究。开发针对NaV1.9相关神经性疼痛的药物疗法，我们的目的是使用携带Scn11ap.R222S突变的小鼠建立一种新的模型,该小鼠最初是在家族性发作性肢体疼痛患者中发现的,其特征是由疲劳或恶劣天气条件引起的阵发性疼痛.我们研究了冷暴露的影响(4°C，过夜）对Scn11ap.R222S突变体（R222S）和野生型C57BL/6N（WT）小鼠的行为和生化表型。我们还测试了对乙酰氨基酚（125，250mg/kg，口头，p.o.）和日本传统医学，goshajinkigan（0.5或1.0g/kg，p.o.),是治疗神经性疼痛患者的镇痛药物，在R222S小鼠冷诱发机械性异常性疼痛模型中。与WT小鼠相比，冷暴露的R222S小鼠表现出增强的机械异常性疼痛和热超敏反应。R222S小鼠在室温下饲养24小时后机械退缩阈值的降低是可逆的。白细胞介素-1β水平无明显变化,白细胞介素-6,肿瘤坏死因子-α,冷暴露后WT和R222S小鼠的血浆或脊髓中的干扰素-γ。对乙酰氨基酚（250mg/kg）和goshajinkigan（1.0g/kg）均显着减轻R222S小鼠的机械性异常疼痛。具有Scn11ap.R222S突变的小鼠冷诱导的机械异常性疼痛模型是新颖的，可用于评估与NaV1.9相关的顽固性神经病的镇痛药物。
