Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 173, Issue 11, Pages 1835-1849Publisher
WILEY
DOI: 10.1111/bph.13482
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Funding
- Japanese Ministry of Education [25860395, 25460110]
- Grants-in-Aid for Scientific Research [25460110, 24590118, 15K07968, 25860395] Funding Source: KAKEN
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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 DSSinduced 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.
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