Voltage-Gated Sodium Channels Regulating Action Potential Generation in Itch-, Nociceptive-, and Low-Threshold Mechanosensitive Cutaneous C-Fibers

We evaluated the effect of voltage-gated sodium channel 1 (Na(v)1) blockers in three nonoverlapping C-fiber subtypes in the mouse skin: chloroquine (CQ)-sensitive C-fibers with high mechanical thresholds-itch C-fibers; second, CQ-insensitive, capsaicin-sensitive C-fibers with high mechanical thresholds-nociceptors; and CQ and capsaicin-insensitive C-fibers with a very low mechanical threshold-C-LTMs. Na(v)1-blocking drugs were applied to the nerve terminal receptive fields using an innervated isolated dorsal mouse skin-nerve preparation where the drugs are delivered into the skin intra-arterially. We combined these studies with an analysis of the mRNA expression of the alpha-subunits of Na(v)1 in individual dorsal root ganglia neurons labeled from the same region of the skin. Our results show that virtually all nociceptors and itch C-fibers expressed the tetrodotoxin (TTX)-resistant channels Na(v)1.8 and Na(v)1.9. However, TTX applied selectively into the skin abolished the action potential firing in response to mechanical stimulation in 75% of the itch C-fibers, 100% of the nociceptors, and 100% of C-LTMs. Na(v)1.7 was the most commonly expressed TTX-sensitive Na(v)1 in all three C-fiber subtypes innervating the dorsal skin. Selectively blocking Na(v)1.7 abolished responses in about 40% of itch C-fibers, 65% of nociceptors, but only 20% of C-LTMs. Blocking Na(v)1.8 alone had no affect on the firing sensitivity of the C-fibers. However, in itch and nociceptive C-fibers where the activation was not inhibited with a Na(v)1.7 blocker, adding the Na(v)1.8 blocker silenced action potential discharge.