Examination of the contribution of Nav1.7 to axonal propagation in nociceptors

Abstract Na v 1.7 is a promising drug target for the treatment of pain. However, there is a mismatch between the analgesia produced by Na v 1.7 loss-of-function and the peripherally restricted Na v 1.7 inhibitors, which may reflect a lack of understanding of the function of Na v 1.7 in the transmission of nociceptive information. In the periphery, the role of Na v 1.7 in transduction at nociceptive peripheral terminals has been comprehensively examined, but its role in axonal propagation in these neurons is less clearly defined. In this study, we examined the contribution of Na v 1.7 to axonal propagation in nociceptors using sodium channel blockers in in vivo electrophysiological and calcium imaging recordings in mice. Using the sodium channel blocker tetrodotoxin (TTX) (1-10 µM) to inhibit Na v 1.7 and other tetrodotoxin-sensitive sodium channels along the sciatic nerve, we first showed that around two-thirds of nociceptive L4 dorsal root ganglion neurons innervating the skin, but a lower proportion innervating the muscle (45%), are blocked by TTX. By contrast, nearly all large-sized cutaneous afferents (95%-100%) were blocked by axonal TTX. Many cutaneous nociceptors resistant to TTX were polymodal (57%) and capsaicin sensitive (57%). Next, we applied PF-05198007 (300 nM-1 µM) to the sciatic nerve between stimulating and recording sites to selectively block axonal Na v 1.7 channels. One hundred to three hundred nanomolar PF-05198007 blocked propagation in 63% of C-fiber sensory neurons, whereas similar concentrations produced minimal block (5%) in rapidly conducting A-fiber neurons. We conclude that Na v 1.7 is essential for axonal propagation in around two-thirds of nociceptive cutaneous C-fiber neurons and a lower proportion (≤45%) of nociceptive neurons innervating muscle.