Sodium channel Nav1.6 in sensory neurons contributes to vincristine-induced allodynia.
Sodium channel Nav1.6 in sensory neurons contributes to vincristine-induced allodynia.
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DOI：
10.1093/brain/awaa208
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发表时间：
2020-08-01
期刊：
影响因子：
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通讯作者：
Dib-Hajj, Sulayman D
中科院分区：
文献类型：
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作者：
Chen, Lubin;Huang, Jianying;Dib-Hajj, Sulayman D
阿曲斯汀是一种广泛使用的化疗药物，可引起疼痛性周围神经病变。其潜在机制尚未得到很好的理解。在这项研究中，我们调查是否电压门控钠通道参与长春新碱诱导的神经病变的发展。我们建立了一种小鼠模型，其中重复全身长春新碱治疗导致发生显著的机械性异常性疼痛。在本研究中使用的长春新碱剂量下，组织学检查未显示近端坐骨神经分支或远端趾神经束的重大结构变化。免疫组织化学研究和体内双光子成像证实，在整个长春新碱治疗过程中，表皮内神经末梢的密度或形态没有显著变化。这些观察结果表明，神经变性不是该模型中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处理后背根神经节神经元中河豚毒素敏感性（TTX-S）和抗性（TTX-R）钠电流的第一个详细表征。伴随着行为痛觉过敏表型，长春新碱处理的动物的小型和中型背根神经节神经元的电压钳记录显示TTX-S Na+电流在中型但不是小型神经元中显著上调。TTX-S Na+电流密度的增加可能由Nav1.6介导，因为在不存在Nav1.6通道的情况下，长春新碱未能改变中背根神经节神经元中的TTX-S Na+电流密度，重要的是，条件性Nav1.6敲除小鼠中的机械性异常性疼痛显著减弱。我们的数据表明，TTX-S钠通道Nav1.6参与了长春新碱处理后背根神经节神经元的功能变化，并有助于维持长春新碱诱导的机械异常性疼痛。
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 Nav1.6, because in the absence of Nav1.6 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 Nav1.6 knockout mice. Our data show that TTX-S sodium channel Nav1.6 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.