title: Role of TRPV1 and TRPA1 in visceral hypersensitivity to colorectal distension during experimental colitis in rats.
abstract: The aim of the present study is to investigate the effects of TRPV1 and TRPA1 receptor antagonists and their synergism on the visceromotor responses during experimental colitis in rats. Colitis was induced in rats by a TNBS/ethanol enema at day 0 and was assessed at day 3 using endoscopy, histology and a myeloperoxidase assay. The visceromotor response to colorectal distension (10-80 mmHg) was evaluated in conscious rats before (control condition) and 3 days after 2,4,6-trinitrobenzene sulfonic acid (TNBS) administration (colitis condition). At day 3, visceromotor responses were assessed before and after treatment with a TRPV1 (BCTC) or TRPA1 (TCS-5861528) receptor antagonist either alone or in combination and either after intraperitoneal or intrathecal administration. Endoscopy, microscopy and myeloperoxidase activity indicated severe colonic tissue damage 3 days after TNBS administration. Colorectal distension-evoked visceromotor responses demonstrated a 2.9-fold increase during acute colitis (day 3) compared to control conditions. Intraperitoneal and intrathecal administration of BCTC or TCS-5861528 partially reversed the colitis-induced increase in visceromotor responses compared to control conditions (P<0.05). Intraperitoneal blockade of TRPA1 plus TRPV1 further decreased the enhanced visceromotor responses at high distension pressures (40-80 mmHg) compared to blockade of either TRPV1 or TRPA1 alone. This synergistic effect was not seen after combined intrathecal blockade of TRPA1 plus TRPV1. The present study demonstrates that in the rat, TRPV1 and TRPA1 play a pivotal role in visceral hypersensitivity at the peripheral and spinal cord level during acute TNBS colitis. Target interaction, however, is presumably mediated via a peripheral site of action.
authors.affiliation: Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Vermeulen
authors.forename: Joris G
authors.initials: JG
authors.lastname: De Man
authors.forename: Heiko U
authors.initials: HU
authors.lastname: De Schepper
authors.forename: Hidde
authors.initials: H
authors.lastname: Bult
authors.forename: Tom G
authors.initials: TG
authors.lastname: Moreels
authors.forename: Paul A
authors.initials: PA
authors.lastname: Pelckmans
authors.forename: Benedicte Y
authors.initials: BY
authors.lastname: De Winter
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D003092:Colitis / Q000378:metabolism / Q000503:physiopathology*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D004357:Drug Synergism; D005260:Female; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012007:Rectum / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D012018:Reflex / Q000187:drug effects; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; C475772:N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide; D011687:Purines; D011719:Pyrazines; D011725:Pyridines; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; C480976:Trpa1 protein, rat; C493922:Trpv1 protein, rat; D014302:Trinitrobenzenesulfonic Acid