Stimulus intensity-dependent recruitment of NaV1 subunits in action potential initiation in nerve terminals of vagal C-fibers innervating the esophagus

We investigated voltage-gated sodium channel (Na V 1) subunits that regulate action potential initiation in the nerve terminals of vagal nodose C-fibers innervating the esophagus. Extracellular single fiber recordings were made from the nodose C-fibers, with mechanically sensitive nerve terminals in the isolated innervated guinea pig esophagus. Na V 1 inhibitors were selectively delivered to the tissue-containing nerve terminals. Graded esophageal distention was used for mechanical stimulation. The Na V 1.7 inhibitor PF-05089771 nearly abolished action potential initiation in response to low levels of esophageal distention but only partially inhibited the response to higher levels of esophageal distention. The PF-05089771-insensitive component of the response progressively increased (up to ≈50%) with increasing esophageal distention and was abolished by tetrodotoxin (TTX). In addition to Na V 1.7, nodose C-fiber [transient receptor potential channel-vanilloid subfamily member 1 (TRPV1)-positive] neurons retrogradely labeled from the esophagus expressed mRNA for multiple TTX-sensitive Na V 1s. The group Na V 1.1, Na V 1.2, and Na V 1.3 inhibitor ICA-121431 inhibited but did not abolish the PF-05089771-insensitive component of the response to high level of esophageal distention. However, combination of ICA-121431 with compound 801, which also inhibits Na V 1.7 and Na V 1.6, nearly abolished the response to the high level of esophageal distention. Our data indicate that the action potential initiation in esophageal nodose C-fibers evoked by low (innocuous) levels of esophageal distention is mediated by Na V 1.7. However, the response evoked by higher (noxious) levels of esophageal distention has a progressively increasing Na V 1.7-independent component that involves multiple TTX-sensitive Na V 1s. The stimulus intensity-dependent recruitment of Na V 1s may offer novel opportunities for strategic targeting of Na V 1 subunits for inhibition of nociceptive signaling in visceral C-fibers. NEW & NOTEWORTHY We report that pharmacologically distinguishable voltage-gated sodium channels (Na V 1) mediate action potential initiation at low (innocuous) versus high (noxious) intensity of esophageal distention in nerve terminals of vagal nodose C-fibers. Action potential initiation at low intensity is entirely dependent on Na V 1.7; however, additional tetrodotoxin (TTX)-sensitive Na V 1s are recruited at higher intensity of distention. This is the first demonstration that Na V 1s underlying action potential initiation in visceral C-fibers depend on the intensity of the stimulus.