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‐HT 3 receptors in the pathogenic mechanisms involved in colonic inflammation, especially in relation to substance P (SP) and the neurokinin‐1 (NK 1 ) receptor. Experimental Approach The effects of 5‐HT 3 and NK 1 receptor antagonists were examined in dextran sulphate sodium (DSS)‐induced colitis in mice. Inflammatory mediator expression and the distribution of 5‐HT 3 and NK 1 receptors were also determined. Key Results Daily administration of ramosetron and ondansetron (5‐HT 3 antagonists) dose‐dependently attenuated the severity of DSS‐induced colitis and up‐regulation of inflammatory mediator expression. Immunohistochemical analysis showed 5‐HT 3 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‐HT 3 receptors and SP but not of those that were double positive for 5‐HT 3 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 NK 1 antagonist. Immunohistochemical studies further revealed that DSS treatment markedly increased NK 1 receptor expression in CD11b‐positive cells. Conclusions and Implications These findings indicate that the 5‐HT/5‐HT 3 receptor and SP/NK 1 receptor pathways play pathogenic roles in colonic inflammation. 5‐HT acts via 5‐HT 3 receptors to up‐regulate inflammatory mediators and promote colonic inflammation. These effects may be further mediated by activation of macrophage NK 1 receptors via SP released from 5‐HT 3 receptor‐positive nerve fibres.