Nav1.7 is a promising drug target for the treatment of pain. However, there is a mismatch between the analgesia produced by Nav1.7 loss-of-function and the peripherally restricted Nav1.7 inhibitors, which may reflect a lack of understanding of the function of Nav1.7 in the transmission of nociceptive information. In the periphery, the role of Nav1.7 in transduction at nociceptive peripheral terminals has been comprehensively examined, but its role in axonal propagation in these neurons is less clearly defined.In this study, we examined the contribution of Nav1.7 to axonal propagation in nociceptors utilising sodium channel blockers in in vivo electrophysiological and calcium imaging recordings in mice. Using the sodium channel blocker TTX (1-10µM) to inhibit Nav1.7 and other TTX-S sodium channels along the sciatic nerve, we first showed that around 2/3rds of nociceptive L4 DRG neurons innervating the skin, but a lower proportion innervating the muscle (45%), are blocked by TTX. In contrast, nearly all large-sized cutaneous afferents (95-100%) were blocked by axonal TTX. Many cutaneous nociceptors resistant to TTX were polymodal (57%) and capsaicin sensitive (57%).Next, we applied PF-05198007 (300nM-1µM) to the sciatic nerve between stimulating and recording sites to selectively block axonal Nav1.7 channels. 100-300nM PF-05198007 blocked propagation in 63% of C-fiber sensory neurons, whereas similar concentrations produced minimal block (5%) in rapidly conducting A-fiber neurons. We conclude that Nav1.7 is essential for axonal propagation in around 2/3rds of nociceptive cutaneous C-fiber neurons, and a lower proportion (≤45%) of nociceptive neurons innervating muscle.

中文翻译：

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检查 Nav1.7 对伤害感受器轴突传播的贡献。

Nav1.7是一个有前途的治疗疼痛的药物靶点。然而，Nav1.7 功能丧失产生的镇痛作用与外周限制性 Nav1.7 抑制剂之间存在不匹配，这可能反映出对 Nav1.7 在伤害性信息传递中的功能缺乏了解。在外周，Nav1.7 在伤害性外周末梢转导中的作用已得到全面研究，但其在这些神经元轴突传播中的作用尚不明确。在本研究中，我们检查了 Nav1.7 对轴突传播的贡献在小鼠体内电生理和钙成像记录中利用钠通道阻滞剂的伤害感受器。使用钠通道阻滞剂 TTX (1-10μM) 抑制沿坐骨神经的 Nav1.7 和其他 TTX-S 钠通道，我们首先表明，大约 2/3 的伤害性 L4 DRG 神经元支配皮肤，但较少比例的神经元支配皮肤。肌肉 (45%) 被 TTX 阻断。相比之下，几乎所有大尺寸皮肤传入神经 (95-100%) 都被轴突 TTX 阻断。许多对 TTX 具有抗性的皮肤伤害感受器是多模式的 (57%) 和辣椒素敏感的 (57%)。 接下来，我们将 PF-05198007 (300nM-1μM) 应用于刺激和记录部位之间的坐骨神经，以选择性阻断轴突 Nav1.7 通道。100-300nM PF-05198007 阻断 63% 的 C 纤维感觉神经元的传播，而相似浓度对快速传导的 A 纤维神经元产生最小的阻断 (5%)。我们得出的结论是，Nav1.7 对于大约 2/3 的伤害性皮肤 C 纤维神经元和较低比例（≤45%）的支配肌肉的伤害性神经元的轴突传播至关重要。