Pain and Neurorestoration Group, King's College London, London, UK.
Nat Rev Neurosci. 2021 May;22(5):263-274. doi: 10.1038/s41583-021-00444-w. Epub 2021 Mar 29.
Evidence from human genetic pain disorders shows that voltage-gated sodium channel α-subtypes Nav1.7, Nav1.8 and Nav1.9 are important in the peripheral signalling of pain. Nav1.7 is of particular interest because individuals with Nav1.7 loss-of-function mutations are congenitally insensitive to acute and chronic pain, and there is considerable hope that phenocopying these effects with a pharmacological antagonist will produce a new class of analgesic drug. However, studies in these rare individuals do not reveal how and where voltage-gated sodium channels contribute to pain signalling, which is of critical importance for drug development. More than a decade of research utilizing rodent genetic models and pharmacological tools to study voltage-gated sodium channels in pain has begun to unravel the role of different subtypes. Here, we review the contribution of individual channel subtypes in three key physiological processes necessary for transmission of sensory information to the CNS: transduction of stimuli at peripheral nerve terminals, axonal transmission of action potentials and neurotransmitter release from central terminals. These data suggest that drugs seeking to recapitulate the analgesic effects of loss of function of Nav1.7 will need to be brain-penetrant - which most of those developed to date are not.
来自人类遗传性疼痛障碍的证据表明，电压门控钠离子通道 α 亚基 Nav1.7、Nav1.8 和 Nav1.9 在疼痛的外周信号传递中很重要。Nav1.7 尤其引人注目，因为 Nav1.7 功能丧失突变的个体对急性和慢性疼痛天生不敏感，人们非常希望用药理学拮抗剂复制这些效果，从而产生一类新的镇痛药。然而，对这些罕见个体的研究并没有揭示电压门控钠离子通道如何以及在何处有助于疼痛信号传递，这对药物开发至关重要。十多年来，利用啮齿动物遗传模型和药理学工具研究疼痛中的电压门控钠离子通道的研究已经开始揭示不同亚型的作用。在这里，我们回顾了个体通道亚型在三个关键生理过程中的作用，这些过程对于将感觉信息传递到中枢神经系统是必要的：外周神经末梢刺激的转导、动作电位的轴突传递和中枢末端神经递质的释放。这些数据表明，试图重现 Nav1.7 功能丧失的镇痛作用的药物需要具有脑穿透性——而迄今为止开发的大多数药物都没有。
