Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

An Erratum to this article was published on 09 December 2012

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  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.

    Article  PubMed  CAS  Google Scholar 

  2. Tytgat GN. Review article: treatment of mild and severe cases of GERD. Aliment Pharmacol Ther. 2002;16:73–78.

    Article  PubMed  Google Scholar 

  3. Yoshida N, Yoshikawa T. Defense mechanism of the esophageal mucosa and esophageal inflammation. J Gastroenterol. 2003;38:31–34.

    PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  5. Yoshida N. Inflammation and oxidative stress in gastroesophageal reflux disease. J Clin Biochem Nutr. 2007;40:13–23.

    Article  PubMed  CAS  Google Scholar 

  6. Barlow WL, Orlando RC. The pathogenesis of heartburn in nonerosive reflux disease: a unifying hypothesis. Gatroenterology. 2005;128:771–778.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  10. Bhat YM, Bielefeldt K. Capsaicin receptor (TRPV1) and non-erosive reflux disease. Eur J Gastroenterol Hepatol. 2006;18:263–270.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  13. Muñoz M, Coveñas R. NK-1 receptor antagonists: a new paradigm in pharmacological therapy. Curr Med Chem. 2011;18:1820–1831.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  19. Bunnett NW. Protease-activated receptors: how proteases signal to cells to cause inflammation and pain. Semin Throm Hemost. 2006;32:39–48.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, 15-749 Honmachi Higashiyama-ku, Kyoto, 605-0981, Japan

    Norimasa Yoshida & Takahiro Suzuki

  2. Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Norimasa Yoshida, Masaaki Kuroda, Kazuhiro Kamada, Kazuhiko Uchiyama, Osamu Handa, Tomohisa Takagi & Toshikazu Yoshikawa

  3. Department of Applied Biology, Kyoto Institute of Technology, Kyoto, Japan

    Hirofumi Kuramoto

Authors
  1. Norimasa Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masaaki Kuroda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takahiro Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazuhiro Kamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kazuhiko Uchiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Osamu Handa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tomohisa Takagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Toshikazu Yoshikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hirofumi Kuramoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Norimasa Yoshida.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoshida, N., Kuroda, M., Suzuki, T. et al. Role of Nociceptors/Neuropeptides in the Pathogenesis of Visceral Hypersensitivity of Nonerosive Reflux Disease. Dig Dis Sci 58, 2237–2243 (2013). https://doi.org/10.1007/s10620-012-2337-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-012-2337-7

Keywords

Search

Navigation