Role of nociceptors/neuropeptides in the pathogenesis of visceral hypersensitivity of nonerosive reflux disease.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, 15-749 Honmachi Higashiyama-ku, Kyoto, 605-0981, Japan. nyoshida@koto.kpu-m.ac.jp
Norimasa
N
Yoshida
Masaaki
M
Kuroda
Takahiro
T
Suzuki
Kazuhiro
K
Kamada
Kazuhiko
K
Uchiyama
Osamu
O
Handa
Tomohisa
T
Takagi
Toshikazu
T
Yoshikawa
Hirofumi
H
Kuramoto
D000368:Aged; D004947:Esophagus / Q000378:metabolism; D005260:Female; D005764:Gastroesophageal Reflux / Q000473:pathology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D009619:Nociceptors / Q000378:metabolism*; D010146:Pain / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D009479:Neuropeptides; D012333:RNA, Messenger