QX-314 inhibits acid-induced esophageal hypersensitivity by regulating TRPV1/NaV1.8 receptor pathway.

Gastroesophageal reflux disease (GERD) is characterized by the reflux of stomach contents, leading to discomfort and potential complications. The intractable discomfort may be related to esophageal hypersensitivity. TRPV1 plays an important role in acid -induced esophageal hypersensitivity, and QX-314 can produce sensory-selective blocked by TRPV1 channels. The present study aims to investigate the role of QX-314 in inhibiting esophageal sensory conduction by constructing GERD guinea pig model. GERD guinea pig model was evaluated by the expression of inflammatory markers and the inflammation scores in the esophagus. The co-localization of TRPV1 and NaV1.8 in the esophagus, nodose ganglion, and jugular ganglion was examined using immunofluorescence, while their expression levels were quantified through Western Blot and RT-qPCR. Inflammatory infiltration was observed in acid-induced guinea pig esophagitis, and the expression levels of inflammatory factors (IL-1β, IL-6, and TNF-α) decreased after QX-314 intervention, while the anti-inflammatory factor (IL-10) increased. Furthermore, the expression and co-localization of TRPV1 and NaV1.8 in the esophagus and jugular ganglion were markedly up-regulated in the GERD group compared to the control group. Compared to GERD group, QX-314 suppressed the expression of TRPV1 and NaV1.8. No substantial alterations were observed in the nodose ganglion. Our results showed that QX-314 can block NaV1.8 channels and consequently exert an inhibiting effect of esophageal sensory conduction by entering cells of jugular ganglion through TRPV1, and then reduce acid-induced esophageal hypersensitivity. Moreover, QX-314 is effective only in the context of acid exposure in the esophagus, enabling the selective inhibition of esophageal hypersensitivity.