Dual Role of Endogenous Serotonin in 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis

Background and Aims: Changes in gut serotonin (5-HT) content have been described in Inflammatory Bowel Disease (IBD) and in different experimental models of colitis: the critical role of this monoamine in the pathogenesis of chronic gastrointestinal inflammation is gradually emerging. Aim of the present study was to evaluate the contribution of endogenous 5-HT through the activation of its specific receptor subtypes to the local and systemic inflammatory responses in an experimental model of IBD. Materials and Methods: Colitis was induced by intrarectal 2,4,6-TriNitroBenzene Sulfonic acid in mice subacutely treated with selective antagonists of 5-HT(1A) (WAY100135), 5-HT(2A) (Ketanserin), 5-HT(3) (Ondansetron), 5-HT(4) (GR125487), 5-HT(7) (SB269970) receptors and with 5-HT(1A) agonist 8-Hydroxy-2-(di-n-propylamino)tetralin. Results: Blockade of 5-HT(1A) receptors worsened TNBS-induced local and systemic neutrophil recruitment while 5-HT(1A) agonist delayed and mitigated the severity of colitis, counteracting the increase in colonic 5-HT content. On the contrary, blockade of 5-HT(2A) receptors improved global health conditions, reduced colonic morphological alterations, down-regulated neutrophil recruitment, inflammatory cytokines levels and colonic apoptosis. Antagonism of 5-HT(3), 5-HT(4), and 5-HT(7) receptor sites did not remarkably affect the progression and outcome of the pathology or only slightly improved it. Conclusion: The prevailing deleterious contribution given by endogenous 5-HT to inflammation in TNBS-induced colitis is seemingly mediated by 5-HT(2A) and, to a lesser extent, by 5-HT(4) receptors and coexists with the weak beneficial effect elicited by 5-HT(1A) stimulation. These findings suggest how only a selective interference with 5-HT pro-inflammatory actions may represent an additional potential therapeutic option for intestinal inflammatory disorders.