title: 5-HT3 receptors promote colonic inflammation via activation of substance P/neurokinin-1 receptors in dextran sulphate sodium-induced murine colitis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Utsumi
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Kikuko
authors.initials: K
authors.lastname: Amagase
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University, Chiba, Japan.
authors.forename: Syunji
authors.initials: S
authors.lastname: Horie
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kato
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017294:Ondansetron / Q000008:administration & dosage / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013373:Substance P / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D018040:Receptors, Neurokinin-1; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D013373:Substance P; D017294:Ondansetron; C071315:ramosetron; D016264:Dextran Sulfate