AUTHOR=Rapalli Alberto , Bertoni Simona , Arcaro Valentina , Saccani Francesca , Grandi Andrea , Vivo Valentina , Cantoni Anna M. , Barocelli Elisabetta 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=7

YEAR=2016

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2016.00068

DOI=10.3389/fphar.2016.00068

ISSN=1663-9812

ABSTRACT=<p><bold>Background and Aims:</bold> 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.</p><p><bold>Materials and Methods:</bold> Colitis was induced by intrarectal 2,4,6-TriNitroBenzene Sulfonic acid in mice subacutely treated with selective antagonists of 5-HT<sub>1A</sub> (WAY100135), 5-HT<sub>2A</sub> (Ketanserin), 5-HT<sub>3</sub> (Ondansetron), 5-HT<sub>4</sub> (GR125487), 5-HT<sub>7</sub> (SB269970) receptors and with 5-HT<sub>1A</sub> agonist 8-Hydroxy-2-(di-<italic>n</italic>-propylamino)tetralin.</p><p><bold>Results:</bold> Blockade of 5-HT<sub>1A</sub> receptors worsened TNBS-induced local and systemic neutrophil recruitment while 5-HT<sub>1A</sub> agonist delayed and mitigated the severity of colitis, counteracting the increase in colonic 5-HT content. On the contrary, blockade of 5-HT<sub>2A</sub> receptors improved global health conditions, reduced colonic morphological alterations, down-regulated neutrophil recruitment, inflammatory cytokines levels and colonic apoptosis. Antagonism of 5-HT<sub>3</sub>, 5-HT<sub>4</sub>, and 5-HT<sub>7</sub> receptor sites did not remarkably affect the progression and outcome of the pathology or only slightly improved it.</p><p><bold>Conclusion:</bold> The prevailing deleterious contribution given by endogenous 5-HT to inflammation in TNBS-induced colitis is seemingly mediated by 5-HT<sub>2A</sub> and, to a lesser extent, by 5-HT<sub>4</sub> receptors and coexists with the weak beneficial effect elicited by 5-HT<sub>1A</sub> 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.</p>