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

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.

DOI: 10.1111/bph.13482

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