Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
Handb Clin Neurol. 2024;203:89-109. doi: 10.1016/B978-0-323-90820-7.00004-5.
There has been significant progress in our understanding of the molecular basis by which nociceptors transduce and transmit noxious (tissue damaging) stimuli. This is dependent on ion channels, many of which are selectively expressed in nociceptors. Mutations in such proteins have recently been linked to inherited pain disorders in humans. An exemplar is the voltage-gated sodium channel (VGSC) Na1.7. Loss of function mutations in Na1.7 result in congenital inability to experience pain while gain-of-function mutations can cause a number of distinct neuropathic pain disorders, including erythromelalgia, paroxysmal extreme pain disorder, and small-fiber neuropathy. Furthermore, variants in the VGSCs 1.8 and 1.9 have also been linked to human pain disorders. There is a correlation between the impact of mutations on the biophysical properties of the ion channel and the severity of the clinical phenotype. Pain channelopathies are not restricted to VGSCs: a mutation in the ligand-gated ion channel TRPA1, (which responds to environmental irritants) causes a familial episodic pain disorder. Ion channel variants have also been linked to more common neuropathic pain disorders such as painful diabetic neuropathy. Not only do these ion channels present targets for novel analgesics, but stratification based on genotype may improve treatment selection of existing analgesics.
我们对伤害感受器转导和传递有害（组织损伤）刺激的分子基础的理解已经取得了重大进展。这取决于离子通道，其中许多在伤害感受器中选择性表达。这些蛋白质的突变最近与人类遗传性疼痛障碍有关。一个范例是电压门控钠离子通道（VGSC）Na1.7。Na1.7 功能丧失性突变导致先天性无法感知疼痛，而功能获得性突变可引起多种不同的神经性疼痛障碍，包括红斑性肢痛症、阵发性剧痛障碍和小纤维神经病。此外，VGSCs 1.8 和 1.9 的变体也与人类疼痛障碍有关。突变对离子通道的生物物理特性的影响与临床表型的严重程度之间存在相关性。疼痛通道病不限于 VGSCs：配体门控离子通道 TRPA1 的突变（对环境刺激物有反应）导致家族性阵发性疼痛障碍。离子通道变体也与更常见的神经性疼痛障碍有关，如痛性糖尿病性神经病。这些离子通道不仅为新型镇痛药提供了靶点，而且基于基因型的分层可能会改善现有镇痛药的治疗选择。
