钠离子通道NaV1.7与神经病理性疼痛

Sodium Channel NaV1.7 and Neuropathic Pain

钠通道NaV1.7是电压门控性钠通道的亚型之一。大多数钠离子通道NaV1.7表达在背根神经节(DRG)小C纤维的伤害性感受器上,具有缓慢开放和缓慢关闭失活的特点。它能够产生大量的斜坡电流,降低感觉神经元中动作电位产生的阈值,放大外来小的缓慢的去极化斜坡电流,从而增加神经元兴奋性,对疼痛的产生、传递、调节具有关键性作用。随着遗传学研究的不断深入,钠离子通道NaV1.7的功能获得性突变和功能缺失性突变,使其成为了新型镇痛疗法中一个的特别有吸引力的药物靶点,受到人们的广泛关注。而研究发现,NaV1.7通道在不同因素引起的神经病理性疼痛中通过不同途径提高神经元兴奋性,参与神经病理性疼痛,给NaV1.7选择性抑制剂研发带来了巨大阻碍。目前,虽然已有的NaV1.7选择性抑制剂具备有效镇痛作用,且无明显副作用或成瘾问题,但寻找NaV1.7选择性配体极其困难。此外,现有的NaV1.7选择性抑制剂也因神经病理性疼痛类型的不同在抑制效力、靶向性、安全性以及可行性等方面存在差异。提示寻找NaV1.7通道作用于不同神经病理性疼痛的普遍机制或NaV1.7通道特有的受体结合位点,可能是未来NaV1.7选择性抑制剂研发的主要方向。本文就NaV1.7通道在不同因素引起的神经病理性疼痛中的主要作用进行简要综述。

Sodium channel Nav1.7 is one of the subtypes of voltage-gated sodium channel.Most of it is expressed on the nociceptors of small C fibers in dorsal root ganglion(DRG).It has the characteristics of slow opening and slow closing of inactivation.It can produce a large amount of ramp current,reduce the threshold of action potential in sensory neurons,and amplify the external small and slow depolarization ramp current.Thus,it can increase the excitability of neurons and play a key role in the generation,transmission and regulation of pain.With the deepening of genetic research,Nav1.7 channel has become a particularly attractive drug target in new analgesic therapy due to its function acquired mutation and function deletion mutation.However,the study found that Nav1.7 channel improves neuronal excitability and participates in neuropathic pain through different ways in neuropathic pain caused by different factors,which has brought great obstacles to the research and development of Nav1.7 selective inhibitors.Although the existing Nav1.7 selective inhibitors have effective analgesic effects without obvious side effects or addiction problems,it is extremely difficult to find Nav1.7 selective ligands.In addition,the existing Nav1.7 selective inhibitors also differ in inhibitory efficacy,targeting,safety and feasibility due to different types of neuropathic pain.It is suggested that finding the general mechanism of Nav1.7 channel acting on different neuropathic pain or the specific receptor binding site of Nav1.7 channel may be the main direction of the research and development of Nav1.7 selective inhibitors in the future.This paper briefly reviews the main role of Nav1.7 channel in neuropathic pain caused by different factors.