Sodium Channel Nav1.8 Underlies TTX-Resistant Axonal Action Potential Conduction in Somatosensory C-Fibers of Distal Cutaneous Nerves

Voltage-gated sodium (Na-V) channels are responsible for the initiation and conduction of action potentials within primary afferents. The nine NaV channel isoforms recognized in mammals are often functionally divided into tetrodotoxin (TTX)-sensitive (TTX-s) channels (Na(V)1.1-Na(V)1.4, Na(V)1.6-Na(V)1.7) that are blocked by nanomolar concentrations and TTX-resistant (TTX-r) channels (Na(V)1.8 and Na(V)1.9) inhibited by millimolar concentrations, with Na(V)1.5 having an intermediate toxin sensitivity. For small-diameter primary afferent neurons, it is unclear to what extent different Na-V channel isoforms are distributed along the peripheral and central branches of their bifurcated axons. To determine the relative contribution of TTX-s and TTX-r channels to action potential conduction in different axonal compartments, we investigated the effects of TTX on C-fiber-mediated compound action potentials (C-CAPs) of proximal and distal peripheral nerve segments and dorsal roots from mice and pigtail monkeys(Macacanemestrina). In the dorsal roots and proximal peripheral nerves of mice and nonhuman primates, TTX reduced the C-CAP amplitude to 16% of the baseline. In contrast, >30% of the C-CAP was resistant to TTX in distal peripheral branches of monkeys and WT and Na(V)1.9(-/-) mice. In nerves from Na(V)1.8(-/-) mice, TTX-r C-CAPs could not be detected. These data indicate that Na(V)1.8 is the primary isoform underlying TTX-r conduction in distal axons of somatosensory C-fibers. Furthermore, there is a differential spatial distribution of Na(V)1.8 within C-fiber axons, being functionally more prominent in the most distal axons and terminal regions. The enrichment of Na(V)1.8 in distal axons may provide a useful target in the treatment of pain of peripheral origin.