Digestive Diseases and Sciences

, Volume 58, Issue 8, pp 2237–2243 | Cite as

Role of Nociceptors/Neuropeptides in the Pathogenesis of Visceral Hypersensitivity of Nonerosive Reflux Disease

  • Norimasa YoshidaEmail author
  • Masaaki Kuroda
  • Takahiro Suzuki
  • Kazuhiro Kamada
  • Kazuhiko Uchiyama
  • Osamu Handa
  • Tomohisa Takagi
  • Toshikazu Yoshikawa
  • Hirofumi Kuramoto
Original Article


Background and Aims

Esophageal visceral hypersensitivity has been proposed to be a pathogenesis of heartburn in nonerosive reflux disease (NERD), but its further mechanisms are unclear. Recently, it has been suggested that nociceptors and neuropeptides control sensory and pain mechanisms. Therefore, the objective of the present study was to estimate expression of acid-sensitive nociceptors such as transient receptor potential vanilloid 1 (TRPV1) and acid-sensing ion channel 3, protease-activated receptor 2 (PAR2), neuropeptides such as substance P and calcitonin-gene-related peptide, and their receptors such as neurokinin 1 receptor (NK1R) and receptor activity-modifying protein 1 in the esophageal mucosa of NERD patients.


Biopsy samples were taken from NERD patients and healthy control subjects without heartburn. The expression level of nociceptors, neuropeptides, and their receptors were assessed by real-time RT-PCR and enzyme immunoassay. Localization of substance P and CGRP in the esophageal mucosa was determined by immunohistochemical staining.


Expression of mRNA for TRPV1 and PAR2 was significantly elevated in the esophageal mucosa of NERD patients. Substance P protein level and its receptor NK1R mRNA also increased in NERD patients. A positive correlation between the substance P protein level and reflux symptoms was observed. Immunohistochemical study revealed the presence of substance P-positive nerves in the lamina propria of the esophagus.


These findings suggest that visceral hypersensitivity in NERD patients is involved in neurogenic inflammation showing the increase in both substance P release and NK1R expression, which may be associated with the activation of TRPV1 and PAR2.


Nonerosive reflux disease (NERD) Visceral hypersensitivity Substance P Neurokinin 1 receptor (NK1R) Transient receptor potential vanilloid 1 (TRPV1) Protease-activated receptor 2 (PAR2) 


Conflict of interest



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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Norimasa Yoshida
    • 1
    • 2
    Email author
  • Masaaki Kuroda
    • 2
  • Takahiro Suzuki
    • 1
  • Kazuhiro Kamada
    • 2
  • Kazuhiko Uchiyama
    • 2
  • Osamu Handa
    • 2
  • Tomohisa Takagi
    • 2
  • Toshikazu Yoshikawa
    • 2
  • Hirofumi Kuramoto
    • 3
  1. 1.Department of GastroenterologyJapanese Red Cross Kyoto Daiichi HospitalKyotoJapan
  2. 2.Molecular Gastroenterology and HepatologyKyoto Prefectural University of MedicineKyotoJapan
  3. 3.Department of Applied BiologyKyoto Institute of TechnologyKyotoJapan

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