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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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Utsumi D,Matsumoto K,Amagase K,Horie S,Kato S

doi

10.1111/bph.13482

subject

Has Abstract

pub_date

2016-06-01 00:00:00

pages

1835-49

issue

eissn

0007-1188

issn

1476-5381

journal_volume

173

pub_type

杂志文章

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