Differential response of esophageal vagal nociceptive and non-nociceptive nerves to M-type potassium channel activation

The vagal sensory nerves innervate the majority of visceral organs and can be broadly divided into nociceptive and non-nociceptive types. Many of the non-nociceptive nerves in the esophagus and airways are the low-threshold mechanosensors that play an important role in regulating the normal physiological functions of viscera such as breathing and GI motility. The nociceptive nerves are primarily C-fibers that initiate various defensive reflexes in response to noxious stimuli. They become hyperexcitable in visceral inflammation and cause the difficult-to-treat clinical symptoms such as visceral pain and chronic coughs. We have previously shown that opening the M-type K + channels inhibited the inflammatory mediator-evoked vagal nociceptor activation and suppressed the vagal C-fiber-mediated coughing. The fact that both nodose C-fiber and A-fiber neurons express functional M-channels raises the concern that targeting the M-channel to normalize the excitability of vagal nociceptors in diseases may cause unwanted side effects due to a concurrent activation of M-channels in the non-nociceptive A-fibers. However, the nodose A-fiber and C-fiber neurons have distinct action potential waveforms and different sensitivities to the rate and intensity of membrane depolarization, suggesting a distinct profile of ion channel composition in these neurons. We therefore hypothesize that the nodose nociceptive and non-nociceptive nerves may react to the M-channel activation differently. To address this hypothesis we examined the effects of M-channel opener retigabine on the response of esophageal nodose nociceptive and non-nociceptive nerve fibers to the isobaric distension in an ex-vivo vagally innervated mouse esophagus preparation using the extracellular recording technique. The distension-evoked nerve activation was quantified as the number of action potential (AP) during 20 second of distension with step increase in the intra-esophageal pressure to 5, 10, 30 and 60 mmHg with 3 min intervals. All studied fibers (n=44) responded to esophageal distensions with AP discharges in a pressure-dependent manner, and exhibited one of two distinct forms of nerve activity-pressure curves. In 20 fibers the AP number and pressure relationship fitted best to a single exponential rise-to-maximum function with a maximal AP number (APmax) of 1209±98, and the pressure at which 50% activation occurs (P1/2) at 13±2 mmHg. In the rest 24 fibers the nerve activity-pressure relationship fitted best to a three-parameter sigmoidal function with a much lower APmax (531±107, p< 0.001) and a higher P1/2 (42±5 mmHg, p< 0.001). These properties are consistent with the characteristics of non-nociceptive and nociceptive esophageal nodose afferents, respectively. Treatment with retigabine significantly reduced the AP discharges at all distension pressures in 10 nociceptive fibers (p< 0.001, two-way ANOVA), but had no effects on the distension-evoked activation in 10 non-nociceptive fibers (p=0.141). In another 7 nociceptive fibers, treatment with M-channel blocker XE991 moderately increased the distension-induced AP firings (p=0.005) and abolished the inhibition of retigabine on the nerve activation by distensions, indicating that the effect of retigabine on the nociceptive fibers was due to M-channel activation. In conclusion, our results indicate that, despite its significant inhibitory effect on nociceptive nerves, activation of M-channel does not affect the response of esophageal nodose non-nociceptive nerves to the mechanical stimulation. Supported by R35HL155671 and R01HL178673. 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.