Capsaicin-Sensitive Vagal Afferent Nerve-Mediated Interoceptive Signals in the Esophagus

Abstract

Heartburn and non-cardiac chest pain are the predominant symptoms in many esophageal disorders, such as gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), functional heartburn and chest pain, and eosinophilic esophagitis (EoE). At present, neuronal mechanisms underlying the process of interoceptive signals in the esophagus are still less clear. Noxious stimuli can activate a subpopulation of primary afferent neurons at their nerve terminals in the esophagus. The evoked action potentials are transmitted through both the spinal and vagal pathways to their central terminals, which synapse with the neurons in the central nervous system to induce esophageal nociception. Over the last few decades, progress has been made in our understanding on the peripheral and central neuronal mechanisms of esophageal nociception. In this review, we focus on the roles of capsaicin-sensitive vagal primary afferent nodose and jugular C-fiber neurons in processing nociceptive signals in the esophagus. We briefly compare their distinctive phenotypic features and functional responses to mechanical and chemical stimulations in the esophagus. Then, we summarize activation and/or sensitization effects of acid, inflammatory cells (eosinophils and mast cells), and mediators (ATP, 5-HT, bradykinin, adenosine, S1P) on these two nociceptive C-fiber subtypes. Lastly, we discuss the potential roles of capsaicin-sensitive esophageal afferent nerves in processing esophageal sensation and nociception. A better knowledge of the mechanism of nociceptive signal processes in primary afferent nerves in the esophagus will help to develop novel treatment approaches to relieve esophageal nociceptive symptoms, especially those that are refractory to proton pump inhibitors.

Potassium-Competitive Acid Blocker Versus Proton Pump Inhibitor: A Pilot Study on Comparable Efficacy in the Treatment of Gastroesophageal Reflux-Related Cough

“… 30 However, the classic reflux symptoms are directly triggered by noxious refluxates (especially acidic refluxate) activating nociceptive receptors in the esophagus. 34 35 Suppressing gastric acid secretion can reduce the noxious stimulation or injury of esophageal mucosa rather than directly inhibiting neurogenic inflammation, which may be related to the faster resolution of reflux symptoms.…”

Identifying causal relationships between gastroesophageal reflux and extraesophageal diseases: A Mendelian randomization study

“…Considering that both the heart and digestive organs are innervated by vegetative nerves, the nerve conduction processes of both may converge in neurons in the same spinal cord segment and share conduction pathways, thus, the central system may misinterprets pain information from visceral afferents as coming from superficial body tissues and manifests as chest pain. [ 50 ] GERD can also alter coronary blood flow. [ 51 ] Direct stimulation of bronchoconstriction or activation of the vagal reflex by pharyngeal reflux aerosols, leading to asthma and tracheospasm.…”

Causal relationship between gastroesophageal reflux disease, Barrett's esophagus, and epilepsy: A bidirectional Mendelian randomization study

“…Our study provides evidence for the genetic prediction of GERD as a potential risk factor for epilepsy (particularly generalized epilepsy). As one of the main information afferent pathways connecting the digestive tract to the brain, the complex autonomic nervous system transmits information received by nerve endings of the esophageal mucosa from gastric acid‐related stimulation to the nucleus of the solitary tract of the brainstem (Yu et al., 2021 ), where afferent vagal projections are transmitted through the pontine parabrachial nucleus and thalamus to seizure‐generating regions in the basal forebrain and insular cortex (Ohemeng & Parham, 2020 ). It is noteworthy that previous observational studies did not find a statistically significant relationship between GERD and epilepsy (Gorenflo et al., 2022 ).…”