The Role of Voltage‐gated Sodium Channel NaV1.7 in Action Potential Initiation in Vagal C‐fiber Nociceptors vs. Aδ‐fiber Mechanosensors Innervating the Guinea Pig Esophagus
Authors: Kollarik Marian , Pavelkova Nikoleta , Liptak Peter , Ru Fei 
Published: June 2021

The vagal nodose ganglion projects two types of nerve fibers into the esophagus: the capsaicin‐sensitive nodose C‐fibers which encode noxious esophageal distention and respond to acid and inflammatory mediators, and the capsaicin‐insensitive low threshold mechanosensitive nodose Aδ‐fibers which only encode innocuous esophageal distention and do not respond to acid and inflammatory mediators. We evaluated the role of NaV1.7 in the action potential initiation in these two nerve fiber types. Single cell RT‐PCR was performed on nodose neurons retrogradely labeled from the esophagus. Extracellular single fiber recordings were made from the neurons in the vagal nodose ganglia projecting mechanosensitive fibers into the esophagus in the isolated vagally innervated guinea pig esophagus preparation. NaV1 blockers were perfused through the esophageal lumen (esophageal mucosa was removed to allow drug diffusion) in order to allow the drug access to nerve terminals in the esophageal muscle wall, but not to their conducting axons in the recurrent laryngeal and vagus nerves. Graded esophageal distention (range 10–90 mmHg) was used for mechanical stimulation. The mRNA for NaV1.7 was detected in nearly all (93%) C‐fiber (TRPV1‐positive) and all Aδ‐fiber (TRPV1‐neagative) neurons retrogradely labeled from the esophagus. Tetrodotoxin (TTX, 0.1μM) abolished mechanical response in nodose Aδ‐fibers (N=5), but inhibited nodose C‐fibers only by 57±13% (N=5). The response of nodose C‐fibers was almost completely blocked by TTX (1μM). We next used the NaV1.7 blocker PF‐05089771 in a concentration of 3μM which completely blocks NaV1.7‐mediated responses in the guinea pig nerve tissue bioassay (J Physiol. 596:1419). Mechanical response of nodose Aδ‐fibers was not affected by PF‐05089771 at any level of esophageal distention tested (5–60mmHg, N=5). In contrast, mechanical response of nodose C‐fibers was inhibited by PF‐05089771. Importantly, the inhibition of nodose C‐fibers depended on the intensity of mechanical stimulation. PF‐05089771 inhibited the mechanical response significantly more (inhibition by 80±4%, N=6) at lower (physiological) levels of esophageal distention (≈35mmHg) than at higher noxious levels of esophageal distention (≈85mmHg, inhibition by 39±7%, N=12, P<0.01 compared to inhibition at ≈35mmHg). We conclude that the action potential initiation in nerve terminals of esophageal nociceptive C‐fibers and low threshold mechanosensitive Aδ‐fibers differs with respect to the role of NaV1.7. NaV1.7 is not required for initiation of action potentials in esophageal nodose Aδ‐fiber mechanosensors. In contrast, NaV1.7 is required for encoding a substantial proportion (40–80%) of mechanical activation of nodose C‐fiber nociceptors. This proportion depends on the stimulus intensity and is higher at the low intensity (innocuous) and lower at high intensity (noxious) mechanical stimuli.Support or Funding InformationSPARC U01 DK116311This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.