5-HT3 receptors promote colonic inflammation via activation of substance P/neurokinin-1 receptors in dextran sulphate sodium-induced murine colitis.

Abstract

BACKGROUND AND PURPOSE:

5-HT (serotonin) regulates various physiological functions, both directly and via enteric neurons. The present study investigated the role of endogenous 5-HT and 5-HT3 receptors in the pathogenic mechanisms involved in colonic inflammation, especially in relation to substance P (SP) and the neurokinin-1 (NK1 ) receptor.

EXPERIMENTAL APPROACH:

The effects of 5-HT3 and NK1 receptor antagonists were examined in dextran sulphate sodium (DSS)-induced colitis in mice. Inflammatory mediator expression and the distribution of 5-HT3 and NK1 receptors were also determined.

KEY RESULTS:

Daily administration of ramosetron and ondansetron (5-HT3 antagonists) dose-dependently attenuated the severity of DSS-induced colitis and up-regulation of inflammatory mediator expression. Immunohistochemical analysis showed 5-HT3 receptors are mainly expressed in vesicular ACh transporter-positive cholinergic nerve fibres in normal colon. DSS increased the number of colonic nerve fibres that were double positive for 5-HT3 receptors and SP but not of those that were double positive for 5-HT3 receptors and vesicular ACh transporter. DSS increased colonic SP levels and SP-positive nerve fibres; these responses were attenuated by ramosetron. DSS-induced colitis and up-regulation of inflammatory mediators were attenuated by aprepitant, an NK1 antagonist. Immunohistochemical studies further revealed that DSS treatment markedly increased NK1 receptor expression in CD11b-positive cells.

CONCLUSIONS AND IMPLICATIONS:

These findings indicate that the 5-HT/5-HT3 receptor and SP/NK1 receptor pathways play pathogenic roles in colonic inflammation. 5-HT acts via 5-HT3 receptors to up-regulate inflammatory mediators and promote colonic inflammation. These effects may be further mediated by activation of macrophage NK1 receptors via SP released from 5-HT3 receptor-positive nerve fibres.

• Authors: Daichi Utsumi, Kenjiro Matsumoto, Kikuko Amagase, Syunji Horie, Shinichi Kato
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 173 Issue 11 Pg. 1835-49 (06 2016) ISSN: 1476-5381 [Electronic] England
• PMID: 26990520 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 The British Pharmacological Society.

Chemical References

• Benzimidazoles
• Receptors, Neurokinin-1
• Receptors, Serotonin, 5-HT3
• Serotonin 5-HT3 Receptor Antagonists
• Substance P
• Ondansetron
• ramosetron
• Dextran Sulfate

Topics

• Animals
• Benzimidazoles (administration & dosage, pharmacology)
• Colitis (chemically induced, metabolism, pathology)
• Colon (metabolism, pathology)
• Dextran Sulfate
• Dose-Response Relationship, Drug
• Inflammation (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Ondansetron (administration & dosage, pharmacology)
• Receptors, Neurokinin-1 (metabolism)
• Receptors, Serotonin, 5-HT3 (metabolism)
• Serotonin 5-HT3 Receptor Antagonists (administration & dosage, pharmacology)
• Structure-Activity Relationship
• Substance P (metabolism)