Voltage-gated sodium (NaV) 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 (NaV1.1–NaV1.4, NaV1.6–NaV1.7) that are blocked by nanomolar concentrations and TTX-resistant (TTX-r) channels (NaV1.8 and NaV1.9) inhibited by millimolar concentrations, with NaV1.5 having an intermediate toxin sensitivity. For small-diameter primary afferent neurons, it is unclear to what extent different NaV 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 NaV1.9-/- mice. In nerves from NaV1.8-/- mice, TTX-r C-CAPs could not be detected. These data indicate that NaV1.8 is the primary isoform underlying TTX-r conduction in distal axons of somatosensory C-fibers. Furthermore, there is a differential spatial distribution of NaV1.8 within C-fiber axons, being functionally more prominent in the most distal axons and terminal regions. The enrichment of NaV1.8 in distal axons may provide a useful target in the treatment of pain of peripheral origin.
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health(Grant R01NS097221 to J.L.M., F.B., and M.R.; Grant P40 OD013117 to RJ Adams; and F32 Fellowship Grant F32DA036991 to A.H.K.) and the German Research Society (DFG Grant SFB1158/1-TP 01 to M.S. and Grant SFB1158/1-TP 04 to R.C.). We thank the Blaustein Pain Research and Education Fund, the Brain Science Institute and the Neurosurgery Pain Research Institute at the Johns Hopkins University for their support of this study; the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (Grant 1UL1TR001079) for statistical analysis; and R.A. Meyer for critically reading a previous version of this manuscript.
- Nonhuman primate
- Sodium channels