The human nociceptor-specific voltage-gated sodium channel 1.7 (hNa_V1.7) is critical for sensing various types of somatic pain, but it appears not to play a primary role in acute visceral pain. However, its role in chronic visceral pain remains to be determined. We used assay-guided fractionation to isolate a novel hNa_V1.7 inhibitor, Tsp1a, from tarantula venom. Tsp1a is 28-residue peptide that potently inhibits hNa_V1.7 (IC₅₀ = 10 nM), with greater than 100-fold selectivity over hNa_V1.3–hNa_V1.6, 45-fold selectivity over hNa_V1.1, and 24-fold selectivity over hNa_V1.2. Tsp1a is a gating modifier that inhibits Na_V1.7 by inducing a hyperpolarizing shift in the voltage-dependence of channel inactivation and slowing recovery from fast inactivation. NMR studies revealed that Tsp1a adopts a classical knottin fold, and like many knottin peptides, it is exceptionally stable in human serum. Remarkably, intracolonic administration of Tsp1a completely reversed chronic visceral hypersensitivity in a mouse model of irritable bowel syndrome. The ability of Tsp1a to reduce visceral hypersensitivity in a model of irritable bowel syndrome suggests that pharmacological inhibition of hNa_V1.7 at peripheral sensory nerve endings might be a viable approach for eliciting analgesia in patients suffering from chronic visceral pain.

中文翻译：

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电压门控钠通道 NaV1.7 的药理学抑制可减轻肠易激综合征啮齿动物模型的慢性内脏疼痛

人类伤害感受器特异性电压门控钠通道 1.7 (hNa _V 1.7) 对于感知各种类型的躯体疼痛至关重要，但它似乎在急性内脏疼痛中并不起主要作用。然而，它在慢性内脏疼痛中的作用仍有待确定。我们使用化验指导的分级分离从狼蛛毒液中分离出一种新型的 hNa _V 1.7 抑制剂 Tsp1a。Tsp1a 是 28 个残基肽，可有效抑制 hNa _V 1.7 (IC ₅₀ = 10 nM)，选择性比 hNa _V 1.3–hNa _{V 1.6 高 100 倍以上，比 hNa V} 1.1选择性高 45 倍，选择性高24 倍超过 hNa _V 1.2。Tsp1a 是一种门控调节剂，可抑制 Na _V1.7 通过在通道失活的电压依赖性中诱导超极化转变并减缓从快速失活的恢复。NMR 研究表明，Tsp1a 采用经典的knottin 折叠，并且与许多knottin 肽一样，它在人血清中异常稳定。值得注意的是，Tsp1a 的结肠内给药完全逆转了肠易激综合征小鼠模型中的慢性内脏超敏反应。Tsp1a 在肠易激综合征模型中降低内脏超敏反应的能力表明，在外周感觉神经末梢对 hNa _{V 1.7 进行药理学抑制可能是引起慢性内脏疼痛患者镇痛的可行方法。}