Vincristine, a widely used chemotherapeutic agent, produces painful peripheral neuropathy. The underlying mechanisms are not well understood. In this study, we investigated whether voltage-gated sodium channels are involved in the development of vincristine-induced neuropathy. We established a mouse model in which repeated systemic vincristine treatment results in the development of significant mechanical allodynia. Histological examinations did not reveal major structural changes at proximal sciatic nerve branches or distal toe nerve fascicles at the vincristine dose used in this study. Immunohistochemical studies and in vivo two-photon imaging confirmed that there is no significant change in density or morphology of intra-epidermal nerve terminals throughout the course of vincristine treatment. These observations suggest that nerve degeneration is not a prerequisite of vincristine-induced mechanical allodynia in this model. We also provided the first detailed characterization of tetrodotoxin-sensitive (TTX-S) and resistant (TTX-R) sodium currents in dorsal root ganglion neurons following vincristine treatment. Accompanying the behavioural hyperalgesia phenotype, voltage-clamp recordings of small and medium dorsal root ganglion neurons from vincristine-treated animals revealed a significant upregulation of TTX-S Na⁺ current in medium but not small neurons. The increase in TTX-S Na⁺ current density is likely mediated by Na_v1.6, because in the absence of Na_v1.6 channels, vincristine failed to alter TTX-S Na⁺ current density in medium dorsal root ganglion neurons and, importantly, mechanical allodynia was significantly attenuated in conditional Na_v1.6 knockout mice. Our data show that TTX-S sodium channel Na_v1.6 is involved in the functional changes of dorsal root ganglion neurons following vincristine treatment and it contributes to the maintenance of vincristine-induced mechanical allodynia.

中文翻译：

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感觉神经元中的Nav1.6钠通道有助于长春新碱诱发的异常性疼痛。

长春新碱是一种广泛使用的化学治疗剂，可引起周围神经痛。潜在的机制尚不完全清楚。在这项研究中，我们调查了电压门控钠通道是否参与长春新碱诱导的神经病的发展。我们建立了一个小鼠模型，其中反复进行系统长春新碱治疗导致明显的机械性异常性疼痛的发展。组织学检查未显示在该研究中使用的长春新碱剂量下，在坐骨神经近端分支或足趾远端神经束的主要结构变化。免疫组织化学研究和体内双光子成像证实在长春新碱治疗的整个过程中，表皮内神经末梢的密度或形态没有显着变化。这些观察结果表明神经变性不是长春新碱诱导的机械性异常性疼痛的先决条件。我们还提供了长春新碱治疗后背根神经节神经元中河豚毒素敏感（TTX-S）和耐药（TTX-R）钠电流的第一个详细表征。伴随行为痛觉过敏表型，长春新碱处理过的动物的中小背根神经节神经元的电压钳记录显示中型但非小神经元中TTX-S Na ⁺电流显着上调。TTX-S Na ⁺的增加Na _v 1.6可能介导电流密度，因为在没有Na _v 1.6通道的情况下，长春新碱不能改变中背根神经节神经元的TTX-S Na ⁺电流密度，重要的是，条件性Na _v中机械异常性疼痛明显减弱1.6敲除小鼠。我们的数据显示，长春新碱治疗后TTX-S钠通道Na _v 1.6参与了背根神经节神经元的功能变化，并有助于长春新碱诱导的机械性异常性疼痛的维持。