Sodium Channels and Pain

Abstract

Electrical excitability in nerve and muscle depends on the action of voltage-gated sodium-selective ion channels. It is now known that there are nine such ion channels; intriguingly, three of them, Nav1.7, Nav1.8, and Nav1.9, are found relatively selectively in peripheral damage-sensing neurons. Local anesthetics are sodium channel blockers that have proved to be excellent analgesics. However, their systemic use is limited by side effects. Because it is known that peripheral damage-sensing sensory neurons are required to drive most pain conditions, there have been many attempts to target peripheral sodium channels for pain relief. Human genetic advances have supported the idea that multiple sodium channel subtypes are good analgesic drug targets. Human monogenic gain-of-function mutations in Nav1.7, Nav1.8, and Nav1.9 cause ongoing pain conditions, while loss-of-function Nav1.7 mutations produce insensitivity to pain. This compelling genetic evidence has inspired a large number of drug development programs aimed at developing analgesic subtype-selective sodium channel blockers. This article reviews the structure and physiological role of voltage-gated sodium channels and describes recent advances in understanding the contribution of sodium channel isoforms to different pain states. Also described are mechanistic studies aimed at better understanding routes to drug development and the potential of gene therapy in therapeutic approaches to pain control. Two decades of sodium channel–targeted drug development have yet to produce a clinical breakthrough, but recent progress holds promise that useful new analgesics are on the horizon.