Visceral Hypersensitivity in Non-erosive Reflux Disease: Neurogenic Overwhelming in Esophagus?

Abstract

The mechanism underlying the pathogenesis of heartburn and chest pain in gastro-esophageal reflux disease (GERD) has not been clearly established. An important advance in understanding how heartburn is experienced has been accomplished with the reporting of dilated intracellular spaces (DIS) in the esophageal mucosa of patients with erosive GERD and non-erosive reflux disease (NERD) [1]. Although the presence of DIS provides a theoretical pathway for direct entry of hydrogen ions into the mucosa [2], its relationship to esophageal barrier function is still controversial since there are no direct measurements of esophageal acid permeability in vivo to support its contribution to barrier function. Another important breakthrough is the detection of transient receptor potential vanilloid subfamily member-1 receptors (TRPV1) in the esophageal mucosa [3], which may potentially contribute to visceral hypersensitivity as one of the important mechanisms in patients with NERD [4]. This notion is supported by the observation that perception of heartburn and esophageal sensitization can be induced by TRPV1 activation after the exposure to capsaicin and related TRPV1 activators such as heat and acid [5]. TRPV1 activation has also been hypothesized to induce neurogenic inflammation by the release of substance P and calcitonin-gene-related peptide (CGRP) in primary afferent neurons [6]. These neuropeptides mediate nociception and neurogenic inflammation via neurokinin 1 receptor (NK1R) for substance P and receptor activity-modifying protein 1 (RAMP1) for CGRP [7–9]. Therefore, the upregulation of TRPV1 expression in the esophageal mucosa is likely explanation for the phenomenon of visceral sensitization in NERD. Moreover, an induction of proteinase-activated receptor-2 (PAR-2) expression was reported in the esophageal mucosa of GERD patients, which correlated well with mucosal inflammatory changes and elevated tissue interleukin (IL)-8 concentrations, providing a possible mechanism for proinflammatory changes in GERD [10]. Furthermore, PAR-2 also mediates nociception via the release of substance P [11]. Finally, although anion-sensing ion channels (ASICs) have been implicated in the chemosensitivity in primary afferent fibers [12], its clinical implication is yet unclear in GERD and is thought to be more likely referred to the mechanosensitivity of the esophagus. In this issue of Digestive Diseases and Sciences [13], Yoshida et al. test the hypothesis regarding the role of nociceptors and neuropeptides in the pathogenesis of visceral hypersensitivity of NERD by examining the expression of acid-sensitive nociceptors including TRPV1, ASIC3, PAR-2, and neuropeptides such as substance P and CGRP with their cognate receptors NK1R and RAMP1 in the esophageal mucosa of NERD patients as compared with age-matched healthy controls. Not surprisingly, increased mRNA expression for TRPV1 and PAR-2 was present in the esophageal mucosa of NERD patients accompanied by a similar increase in substance P protein level and mRNA of its receptor NK1R. They also reported the presence of substance P-positive and CGRP-positive nerves in lamina propria of the esophageal mucosa of their patients by immunohistochemistry. They reported a positive correlation between substance P protein level and acid reflux score. Their data suggest that visceral hypersensitivity in NERD patients appears to be related to nociception and neurogenic inflammation, which supports their hypothesis C.-L. Chen (&) Department of Medicine, Buddhist Tzu Chi General Hospital and Tzu Chi University, 707, Section 3, Chung-Yang Road, Hualien 970, Taiwan e-mail: harry.clchen@msa.hinet.net