Inhibition of endothelial cell adhesion molecule expression improves colonic hyperalgaesia.
Leucocyte-endothelial cell interactions are prerequisite to leucocyte infiltration and intestinal inflammation. GI270384X is a novel inhibitor of ICAM-1 and E-selectin expression and inhibits leucocyte adhesion and improves experimental colitis. We hypothesized that GI270384X maybe effective in treatment of visceral hyperalgaesia. Visceromotor behavioural responses to colorectal distension (CRD) were obtained in naïve rats or rats treated with zymosan (3 h) or 2,4,6-trinitrobenzene sulphonic acid (TNBS) (4 and 30 days) or rats exposed to acute restraint stress. Studies were also performed in a high-anxiety genetic model of colonic hyperalgaesia using Wistar-Kyoto (WKY) rats. Rats were treated orally with GI270384X or vehicle either prior to or after the administration of sensitizing stimulus. The visceromotor response to CRD was significantly enhanced in all models. GI270384X attenuated the enhanced responses to distension induced by inflammatory stimuli (TNBS and zymosan) and in the high-anxiety WKY rats; however, the drug did not inhibit the hypersensitivity induced by acute restraint stress. GI270384X was most potent in the models of acute inflammatory hyperalgaesia with a minimum efficacious dose (MED) of 0.3 and 1 mg kg(-1) observed in the TNBS and zymosan models respectively. The compound was less potent in the chronic and postinflammatory models with an MED of 10 and 30 mg kg(-1) observed in the WKY and 30-day TNBS models respectively. These findings show for the first time that inhibition of leucocyte-endothelial cell interactions can have a beneficial effect on visceral hyperalgaesia associated with inflammatory and chronic anxiety states, but is less effective against stress-associated visceral hyperalgaesia.
Winchester
W J
WJ
Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Stevenage, UK.
Johnson
A
A
Hicks
G A
GA
Gebhart
G F
GF
Greenwood-van Meerveld
B
B
McLean
P G
PG
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy; D003106:Colon / Q000033:anatomy & histology / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D004108:Dilatation, Pathologic; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D013315:Stress, Psychological; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D019040:E-Selectin; C524446:GI270384X; D011687:Purines; D018799:Intercellular Adhesion Molecule-1; D011092:Polyethylene Glycols; D014302:Trinitrobenzenesulfonic Acid; D015054:Zymosan