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

Abstract

BACKGROUND AND PURPOSE5-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 APPROACHThe 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 RESULTSDaily administration of ramosetron and ondansetron (5-HT 3 antagonists) dose-dependently attenuated the severity of DSSinduced 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 IMPLICATIONSThese 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. The 5-HT 3 receptor is a ligand-gated cation channel and is widely distributed in brain and spinal cord neurones, as well as in the gastrointestinal tract (Farber et al., 2004). In the gastrointestinal tract, the 5-HT 3 receptor is involved in secretory, peristaltic, emetic and pain responses (Siriwardena et al., 1993;Jackson and Yakel, 1995;Hansen, 2003). Indeed, 5-HT 3 receptor antagonists have been used clinically for the treatment of chemotherapy-induced nausea/emesis and irritable bowel syndrome with diarrhoea (Minami et al., 1997;Kozlowski et al., 2000;Fukudo et al., 2014). We recently found that 5-HT 3 receptor antagonists such as ramosetron and ondansetron ameliorated intestinal injuries induced by the anticancer agent, 5-fluorouracil (5-FU), and the nonsteroidal anti-inflammatory drug, indomethacin (Kato et al., 2012;Yasuda et al., 2013). Several studies further showed that 5-HT 3 receptor antagonists reduced the severity of postoperative ileus and colitis (Mousavizadeh et al., 2009;Motavallian et al., 2013;Maehara et al., 2015). These findings suggest that endogenous 5-HT has pro-inflammatory effects that are mediated via 5-HT 3 ...

Intestinal Microbiota Mediates the Susceptibility to Polymicrobial Sepsis‐Induced Liver Injury by Granisetron Generation in Mice

“…S15) (40) and can regulate gut pathophysiology. (41,42) Hence, we speculate that the different susceptibility of intestinal injury observed in Sen and Res mice may partially involve serotonin and 5-HT 3 receptor interaction in the gut and may modulate the 5-HT 3 receptor antagonist, granisetron, production from the gut microbiota.…”

Differential effects of aprepitant, a clinically used neurokinin-1 receptor antagonist on the expression of conditioned psychostimulant versus opioid reward

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Transient receptor potential vanilloid 4 channel regulates vascular endothelial permeability during colonic inflammation in dextran sulphate sodium‐induced murine colitis

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