QX ‐314 inhibits acid‐induced activation of esophageal nociceptive C fiber neurons

Acid reflux in the esophagus can induce painful sensations such as heartburn and non‐cardiac chest pain. These nociceptive symptoms are initiated by activation of TRPV 1‐positive afferent C fibers in the esophagus. The present study aimed to explore a novel C fiber inhibition approach. We hypothesized that activation of TRPV 1 by acid enabled QX ‐314, a membrane impermeable sodium channel blocker, to inhibit acid‐induced activation of esophageal nociceptive C fiber neurons. Method We determined the inhibitory effect of QX ‐314 in the presence of acid in guinea pig esophageal nociceptive vagal jugular C fiber neurons by both patch clamp recording in neuron soma and by extra‐cellular recording at nerve terminals. Key Results Our data demonstrated QX ‐314 alone did not inhibit sodium currents. However, when applied along with capsaicin to activate TRPV 1, QX ‐314 was able to block sodium currents in esophageal‐specific jugular C fiber neurons. We then showed that in the presence of acid, QX ‐314 significantly blocked acid‐evoked activation of jugular C fiber neurons. This effect was attenuated by TRPV 1 antagonist AMG 9810, suggesting acid‐mediated inhibitory effect of QX ‐314 was TRPV 1‐dependent. Finally, we provided evidence at nerve endings that acid‐evoked action potential discharges in esophageal jugular C fibers were inhibited by QX ‐314 when applied in the presence of acid. Conclusion and Inferences Our data demonstrated that activation of TRPV 1 by acid enabled membrane impermeable sodium channel blocker QX ‐314 to inhibit acid‐induced activation in esophageal nociceptive C fibers. This supports a localized application of QX ‐314 in the esophagus to block esophageal nociception in acid reflux disorders.