Inhibition of Cough-Causing Nociceptors by Selective NaV Channel Blockers

The guinea pig is the only species where the afferent nerves subserving coughing have been described. In this species, cough is evoked by two disparate subtypes of vagal nociceptors terminating in the larynx, trachea, and bronchi. One subtype comprises vagal C-fibers with their cell bodies primarily in the neural crest-derived jugular ganglia; the other subtype consists of myelinated Ad fibers with their cell bodies in the placode-derived nodose ganglia. C-fiber–mediated cough in guinea pigs can be evoked by several inflammatory mediators and requires consciousness, consistent with the irritating urge to cough that humans experience when inhaling low concentrations of selective C-fiber stimulants such as capsaicin. In contrast, the Ad fiber–induced coughing can occur subconsciously, is not evoked by inflammatory mediators (so far), but stimulated by rapid changes in pH and by punctate mechanical stimulation, consistent with a rapid protective reflex. Using retrograde tracing dye injections combined with single-neuron RT-PCR, we evaluated NaV1.1–NaV1.9 mRNA expression in these two subtypes of cough-causing neurons. Our studies revealed that NaV1.7, NaV1.8, and NaV1.9 mRNAs were detected in nearly 100% of nodose airway neurons as well as in jugular airway neurons (n=39 and 33, respectively). Nav1.2 was expressed in 28% and 27% of airway nodose and jugular neurons, respectively. NaV1.3 was expressed in 21% and 15% of nodose and jugular tracheal neurons, respectively. Either NaV1.2 or 1.3 was found in 48% and 42% of respective nodose and jugular neurons. The other NaV1 subtypes were either not expressed or expressed in 90%, reduced the peak frequency (Hz) of action potential discharge in jugular C-fibers by ~49% (P< 0.05). Combining the NaV1.8 blocker with a highly selective NaV1.7 blocker (GNE8943) further reduced the peak Hz by ~74% (P< 0.01). In contrast, selectively blocking NaV1.8 alone did not significantly reduce the acid-induced peak frequency of discharge in tracheal nodose Ad fibers; however, the combination of NaV1.8 and NaV1.7 significantly reduced the peak Hz of discharge by ~54% (P < 0.01). Adding tetrodotoxin resulted in 100% blockade in both nodose Ad and jugular C fibers. It is well appreciated that C-fiber–mediated coughing is upregulated in humans with chronic cough, as generally quantified by the striking leftward shift in capsaicin dose–cough response curves. Our results support the hypothesis that selective targeting of NaV1.8 may reduce this C-fiber mediated hypersensitivity (“hypertussivity”). Since NaV1.8 blockade alone did not inhibit the peak Hz of action potential discharge in nodose Ad fibers, the reduction in C-fiber activity may occur without compromising the “protective” vagal Ad fiber–induced coughing. The combination of NaV1.8 and NaV1.7 blockade caused a much stronger inhibition of tracheal C-fiber activity, but this combination also inhibited the acid-induced Ad fiber activation. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.