Vincristine-induced peripheral neuropathy (VIPN) is a common side effect of vincristine treatment, which is accompanied by pain and can be dose-limiting. The molecular mechanisms that underlie vincristine-induced pain are not well understood. We have established an animal model to investigate pathophysiological mechanisms of vincristine induced pain. Our previous studies have shown that the tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channel NaV1.6 in medium-diameter dorsal root ganglion (DRG) neurons contributes to the maintenance of vincristine-induced allodynia. In this study, we investigated the effects of vincristine administration on excitability in small-diameter DRG neurons and whether the tetrodotoxin-resistant (TTX-R) NaV1.8 channels contribute to mechanical allodynia. Current-clamp recordings demonstrated that small DRG neurons become hyper-excitable following vincristine treatment, with both reduced current threshold and increased firing frequency. Using voltage-clamp recordings in small DRG neurons we now show an increase in TTX-R current density and a -7.3 mV hyperpolarizing shift in V1/2 of activation of NaV1.8 channels in vincristine-treated animals, which likely contributes to the hyperexcitability that we observed in these neurons. Notably, vincristine treatment did not enhance excitability of small DRG neurons from NaV1.8 knockout mice, and the development of mechanical allodynia was delayed but not abrogated in these mice. Together, our data suggest that sodium channel NaV1.8 in small DRG neurons contributes to the development of vincristine-induced mechanical allodynia.

中文翻译：

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小背根神经节神经元中的 Nav1.8 有助于长春新碱诱导的机械异常性疼痛

长春新碱引起的周围神经病变（VIPN）是长春新碱治疗的常见副作用，伴有疼痛，并且可以限制剂量。长春新碱引起疼痛的分子机制尚不清楚。我们建立了动物模型来研究长春新碱引起疼痛的病理生理机制。我们之前的研究表明，中等直径背根神经节（DRG）神经元中的河豚毒素敏感（TTX-S）电压门控钠通道NaV1.6有助于维持长春新碱引起的异常性疼痛。在这项研究中，我们研究了长春新碱对小直径 DRG 神经元兴奋性的影响，以及河豚毒素抗性 (TTX-R) NaV1.8 通道是否会导致机械性异常性疼痛。电流钳记录表明，长春新碱治疗后，小 DRG 神经元变得高度兴奋，电流阈值降低，放电频率增加。使用小 DRG 神经元的电压钳记录，我们现在显示长春新碱治疗的动物中 TTX-R 电流密度增加，NaV1.8 通道激活的 V1/2 发生 -7.3 mV 超极化偏移，这可能导致超兴奋性我们在这些神经元中观察到的。值得注意的是，长春新碱治疗并没有增强 NaV1.8 敲除小鼠的小 DRG 神经元的兴奋性，并且这些小鼠中机械性异常性疼痛的发生被延迟但没有消除。总之，我们的数据表明小 DRG 神经元中的钠通道 NaV1.8 有助于长春新碱诱导的机械性异常性疼痛的发生。