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

Abstract

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.

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.

Keywords

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

Notes

Conflict of interest

None.

References

  1. 1.
    Dean BB, Gano AD Jr, Knight K, Ofman JJ, Fass R. Effectiveness of proton pump inhibitors in nonerosive reflux disease. Clin Gastroenterol Hepatol. 2004;2:656–664.PubMedCrossRefGoogle Scholar
  2. 2.
    Tytgat GN. Review article: treatment of mild and severe cases of GERD. Aliment Pharmacol Ther. 2002;16:73–78.PubMedCrossRefGoogle Scholar
  3. 3.
    Yoshida N, Yoshikawa T. Defense mechanism of the esophageal mucosa and esophageal inflammation. J Gastroenterol. 2003;38:31–34.PubMedGoogle Scholar
  4. 4.
    Yoshida N, Uchiyama K, Kuroda M, et al. IL-8 expression in the esophageal mucosa of patients with gastroesophageal reflux disease. Scand J Gastroenterol. 2004;39:816–822.PubMedCrossRefGoogle Scholar
  5. 5.
    Yoshida N. Inflammation and oxidative stress in gastroesophageal reflux disease. J Clin Biochem Nutr. 2007;40:13–23.PubMedCrossRefGoogle Scholar
  6. 6.
    Barlow WL, Orlando RC. The pathogenesis of heartburn in nonerosive reflux disease: a unifying hypothesis. Gatroenterology. 2005;128:771–778.CrossRefGoogle Scholar
  7. 7.
    Trimble KC, Pryde A, Heading RC. Lowered oesophageal sensory thresholds in patients with symptomatic but not excess gastro-oesophageal reflux: evidence for a spectrum of visceral sensitivity in GORD. Gut. 1995;37:7–12.PubMedCrossRefGoogle Scholar
  8. 8.
    Miwa H, Minoo T, Hojo M, et al. Oesophageal hypersensitivity in Japanese patients with non-erosive gastro-oesophageal reflux diseases. Aliment Pharmacol Ther. 2004;20:112–117.PubMedCrossRefGoogle Scholar
  9. 9.
    Matthews PJ, Aziz Q, Facer P, Davis JB, Thompson DG, Anand P. Increased capsaicin receptor TRPV1 nerve fibres in the inflamed human oesophagus. Eur J Gastroenterol Hepatol. 2004;16:897–902.PubMedCrossRefGoogle Scholar
  10. 10.
    Bhat YM, Bielefeldt K. Capsaicin receptor (TRPV1) and non-erosive reflux disease. Eur J Gastroenterol Hepatol. 2006;18:263–270.PubMedCrossRefGoogle Scholar
  11. 11.
    Wick EC, Hoge SG, Grahn SW, et al. Transient receptor potential vanilloid 1, calcitonin gene-related peptide, and substance P mediate nociception in acute pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2006;290:G959–G969.PubMedCrossRefGoogle Scholar
  12. 12.
    Engel MA, Khalil M, Mueller-Tribbensee SM, et al. The proximodistal aggravation of colitis depends on substance P released from TRPV1-expressing sensory neurons. J Gastroenterol. 2012;47:256–265.PubMedCrossRefGoogle Scholar
  13. 13.
    Muñoz M, Coveñas R. NK-1 receptor antagonists: a new paradigm in pharmacological therapy. Curr Med Chem. 2011;18:1820–1831.PubMedCrossRefGoogle Scholar
  14. 14.
    Tillisch K, Labus J, Nam B, et al. Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot study. Aliment Pharmacol Ther. 2012;35:360–367.PubMedCrossRefGoogle Scholar
  15. 15.
    Marquez de Prado B, Hammond DL, Russo AF. Genetic enhancement of calcitonin gene-related peptide-induced central sensitization to mechanical stimuli in mice. J Pain. 2009;10:992–1000.PubMedCrossRefGoogle Scholar
  16. 16.
    Cottrell GS, Alemi F, Kirkland JG, Grady EF, Corvera CU, Bhargava A. Localization of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in human gastrointestinal tract. Peptides. 2012;35:202–211.PubMedCrossRefGoogle Scholar
  17. 17.
    Yoshida N, Yoshikawa T. Basic and translational research on proteinase-activated receptors: implication of proteinase/proteinase-activated receptor in gastrointestinal inflammation. J Pharmacol Sci. 2008;108:415–421.PubMedCrossRefGoogle Scholar
  18. 18.
    Vergnolle N, Bunnett NW, Sharkey KA, et al. Proteinase-activated receptor-2 and hyperalgesia: a novel pain pathway. Nat Med. 2001;7:821–826.PubMedCrossRefGoogle Scholar
  19. 19.
    Bunnett NW. Protease-activated receptors: how proteases signal to cells to cause inflammation and pain. Semin Throm Hemost. 2006;32:39–48.CrossRefGoogle Scholar
  20. 20.
    Huang SC. Protease-activated receptor-1(PAR1) and PAR2 but not PAR 4 mediate relaxations in lower esophageal sphincter. Regul Pept. 2006;142:37–43.CrossRefGoogle Scholar
  21. 21.
    Carlsson R, Dent J, Bolling-Sternevald E, et al. The usefulness of a structured questionnaire in the assessment of symptomatic gastroesophageal reflux disease. Scand J Gastroenterol. 1998;33:1023–1029.PubMedCrossRefGoogle Scholar
  22. 22.
    Revicki DA, Wood M, Wiklund I, Crawley J. Reliability and validity of the gastrointestinal symptom rating scale in patients with gastroesophageal reflux disease. Qual Life Res. 1998;7:75–83.PubMedCrossRefGoogle Scholar
  23. 23.
    Pan XQ, Gonzalez JA, Chang S, Chacko S, Wein AJ, Malykhina AP. Experimental colitis triggers the release of substance P and calcitonin gene-related peptide in the urinary bladder via TRPV1 signaling pathways. Exp Neurol. 2010;225:262–273.PubMedCrossRefGoogle Scholar
  24. 24.
    Humes DJ, Simpson J, Smith J, et al. Visceral hypersensitivity in symptomatic diverticular disease and the role of neuropeptides and low grade inflammation. Neurogastroenterol Motil. 2012;24:318–1630.PubMedCrossRefGoogle Scholar
  25. 25.
    Guarino MP, Cheng L, Ma J, et al. Increased TRPV1 gene expression in esophageal mucosa of patients with non-erosive and erosive reflux disease. Neurogastroenterol Motil. 2010;22:746–751.PubMedCrossRefGoogle Scholar
  26. 26.
    Tohda C, Sasaki M, Konemura T, et al. Axonal transport of VR1 capsaicin receptor mRNA in primary afferents and its participation in inflammation-induced increase in capsaicin sensitivity. J Neurochem. 2001;76:1628–1635.PubMedCrossRefGoogle Scholar
  27. 27.
    Banerjee B, Medda BK, Lazarova Z, Bansal N, Shaker R, Sengupta JN. Effect of reflux-induced inflammation on transient receptor potential vanilloid one (TRPV1) expression in primary sensory neurons innervating the oesophagus of rats. Neurogastroenterol Motil. 2007;19:681–691.PubMedCrossRefGoogle Scholar
  28. 28.
    Suzuki T, Yoshida N, Mizushima K, et al. TRPV1 expression associated with nerve growth factor mediates the esophageal visceral hypersensitivity. Gastroenterology. 2008;134:A-589–A-590.CrossRefGoogle Scholar
  29. 29.
    Yoshida N, Katada K, Handa O, et al. Interleukin-8 production via protease-activated receptor 2 in human esophageal epithelial cells. Int J Mol Med. 2007;19:335–340.PubMedGoogle Scholar
  30. 30.
    Emerenziani S, Sifrim D, Habib FI, et al. Presence of gas in the refluxate enhances reflux perception in non-erosive patients with physiological acid exposure of the oesophagus. Gut. 2008;57:443–447.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Norimasa Yoshida
    • 1
    • 2
  • 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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