Effects of acid on vagal nociceptive afferent subtypes in guinea pig esophagus

Abstract

Acid reflux-induced heartburn and noncardiac chest pain are processed peripherally by sensory nerve endings in the wall of the esophagus, but the underlying mechanism is still unclear. This study aims to determine the effects of acid on esophageal vagal nociceptive afferent subtypes. Extracellular single-unit recordings were performed in guinea pig vagal nodose or jugular C fiber neurons by using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. We recorded action potentials (AP) of esophageal nodose or jugular C fibers evoked by acid perfusion and compared esophageal distension-evoked AP before and after acid perfusion. Acid perfusion for 30 min (pH range 7.4 to 5.8) did not evoke AP in nodose C fibers but significantly decreased their responses to esophageal distension, which could be recovered after washing out acid for 90 min. In jugular C fibers, acid perfusion not only evoked AP but also inhibited their responses to esophageal distension, which were not recovered after washing out acid for 120 min. Lower concentration of capsaicin perfusion mimicked acid-induced effects in nodose and jugular C fibers. Pretreatment with TRPV1 antagonist AMG9810, but not acid-sensing ion channel (ASIC) inhibitor amiloride, significantly inhibited acid-induced effects in nodose and jugular C fiber. These results demonstrate that esophageal vagal nociceptive afferent nerve subtypes display distinctive responses to acid. Acid activates jugular, but not nodose, C fibers and inhibits both of their responses to esophageal distension. These effects are mediated mainly through TRPV1. This inhibitory effect is a novel finding and may contribute to esophageal sensory/motor dysfunction in acid reflux diseases.

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

“…These clinical findings indicated that TRPV1 plays a crucial role in acid‐evoked activation of esophageal nociceptors. Recent studies from ours and others have demonstrated that esophageal nociceptors are usually TRPV1‐positive afferent C fibers, and acid selectively activates esophageal nociceptive neural crest vagal jugular (and DRG) C fiber subtypes through TRPV1‐mediated mechanism . As a non‐selective cation channel, TRPV1 not only mediates capsaicin‐evoked activation of nociceptive C fiber neurons but also responds to thermal stimulation (heat) and protons (acid) .…”

“…Even though all these nociceptive C fibers are able to respond to noxious mechanical and chemical (such as capsaicin) stimuli, only neural crest (vagal jugular and DRG) C fibers are activated by acid at low pH of 4.4. This activation effect is largely mediated via a TRPV1‐dependent mechanism . These results suggest that antagonizing TRPV1 could be an effective way to inhibit acid‐induced esophageal nociception.…”

“…Retrograde labeling of vagal jugular neurons from the esophagus with DiI (1,1′‐dioctadecyl‐3,3,3′,3′‐tetramethylindocarbocyanine perchlorate) (Molecular Probe, Eugene, OR) was performed in 12 guinea pigs according to our previously described method . Briefly, animals were anaesthetized with ketamine (80 mg/kg) and xylazine (5 mg/kg) dissolved in phosphate‐buffered saline (PBS).…”

“…Whole‐cell patch clamp recordings in Dil‐labeled esophageal jugular neurons were performed according to our previous described methods . Briefly, the borosilicate glass (WPI, Sarasota, FL) electrodes were pulled with a resistance of 2‐3 MΩ when filled with the pipette solution (mM): 140 CsCl, 1 MgCl 2 , 5 MgATP, 2 EGTA, and 10 HEPES (pH 7.2 with CsOH).…”

In vitro multichannel single-unit recordings of action potentials from the mouse sciatic nerve

“…Single-unit recordings from peripheral nerves have been mainly conducted in animals in vitro or in vivo (e.g., recordings from vagus nerves [23, 24], aortic depressor nerves [25], spinal nerves [26, 27], splanchnic nerves [28], and pelvic nerves [29–31]). To achieve a high signal-to-noise ratio, the technically challenging approach taken was to carefully isolate nerve trunks, gently splitting the trunk into fine nerve bundles, and teasing a bundle into microns thick fine filaments.…”