Functional role of Nav1.8 channels in action potentials of mouse CGRP-lineage dorsal root ganglion neurons.

Primary sensory neurons that sense noxious stimuli (nociceptors) are unusual in possessing two major components of voltage-dependent sodium channel current with different voltage dependence and kinetics. We used pharmacology to characterize the roles of defined sodium channel types in generating action potentials and controlling repetitive firing in putative peptidergic nociceptors, using mice in which CGRP-lineage neurons are fluorescently labelled. We found that the major components of sodium current were carried by Nav1.8 channels, identified by sensitivity to VX-548 (suzetrigine), and by Nav1.7 channels, identified by sensitivity to the toxin GsAF-1, with an additional smaller component of current carried by tetrodotoxin-sensitive channels resistant to GsAF-1. Action potential clamp experiments were used to quantify the size and time course of the Nav1.8 component of sodium current during firing of single and repetitive action potentials. In most neurons, Nav1.8 current carried the majority of overall sodium entry during action potentials and nearly all of the sodium current supporting action potentials during repetitive firing. Although total tetrodotoxin-sensitive current (mostly but not entirely carried by Nav1.7 channels) activated with smaller depolarizations and much more rapidly than Nav1.8 current, Nav1.8 current was equally important in setting the action potential threshold and was dominant in the action potential upstroke because of its greater size. By comparison with similar experiments in human dorsal root ganglion neurons, the results suggest Nav1.8 channels play a more dominant role in firing of mouse peptidergic nociceptors than in human C-type nociceptors, suggesting limitations of pharmacology of mouse nociceptors for predicting effects on human nociceptor excitability. KEY POINTS: The new Nav1.8 inhibitor VX-548 (suzetrigine) was used to define the role of Nav1.8 currents in generating action potentials in mouse CGRP-lineage dorsal root ganglion neurons. Nav1.8 current typically carried the majority of sodium current evoked by voltage steps, with remaining current mainly carried by Nav1.7 channels (identified by sensitivity to GsAF-1) together with a small component from tetrodotoxin-sensitive channels not inhibited by GsAF-1. Nav1.8 current contributes to determining the action potential threshold, provides the majority of sodium current during the rising phase of the action potential and flows during the shoulder of the action potential typical of C-fibre nociceptors. Inhibition of Nav1.8 sodium current by VX-548 produces a counter-intuitive decrease in refractory period, probably resulting from reduction of potassium channel activation caused by a smaller peak and narrower action potential when Nav1.8 current is inhibited.