title: Vanilloid receptor 1 antagonists attenuate disease severity in dextran sulphate sodium-induced colitis in mice.
abstract: Neurogenic mechanisms have been implicated in the induction of inflammatory bowel disease (IBD). Vanilloid receptor type 1 (TRPV1) has been visualized on nerve terminals of intrinsic and extrinsic afferent neurones innervating the gastrointestinal tract and local administration of a TRPV1 antagonist, capsazepine, reduces the severity of dextran sulphate sodium (DSS)-induced colitis in rats (Gut 2003; 52: 713-9(1)). Our aim was to test whether systemically or orally administered TRPV1 antagonists attenuate experimental colitis induced by 5% DSS in Balb/c mice. Intraperitoneal capsazepine (2.5 mg kg(-1), bid), significantly reduced the overall macroscopic damage severity compared with vehicle-treated animals (80% inhibition, P < 0.05); however, there was no effect on myeloperoxidase (MPO) levels. An experimental TRPV1 antagonist given orally was tested against DSS-induced colitis, and shown to reverse the macroscopic damage score at doses of 0.5 and 5.0 mg kg(-1). Epithelial damage assessed microscopically was significantly reduced. MPO levels were attenuated by approximately 50%, and diarrhoea scores were reduced by as much as 70%. These results suggest that pharmacological modulation of TRPV1 attenuates indices of experimental colitis in mice, and that development of orally active TRPV1 antagonists might have therapeutic potential for the treatment of IBD.
authors.affiliation: Drug Discovery Division, Johnson and Johnson Pharmaceutical Research and Development, PA 19477, USA. ekimball@prdus.jnj.com
authors.forename: E S
authors.initials: ES
authors.lastname: Kimball
authors.forename: N H
authors.initials: NH
authors.lastname: Wallace
authors.forename: C R
authors.initials: CR
authors.lastname: Schneider
authors.forename: M R
authors.initials: MR
authors.lastname: D'Andrea
authors.forename: P J
authors.initials: PJ
authors.lastname: Hornby
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D015212:Inflammatory Bowel Diseases / Q000473:pathology / Q000517:prevention & control; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D050916:TRPV Cation Channels
chemical_list: D000925:Anticoagulants; D007473:Ion Channels; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D016264:Dextran Sulfate; D009195:Peroxidase; C071423:capsazepine; D002211:Capsaicin