Dexamethasone prevents visceral hyperalgesia but not colonic permeability increase induced by luminal protease-activated receptor-2 agonist in rats.
BACKGROUND
Low-grade inflammation may play a role in the pathogenesis of irritable bowel syndrome (IBS). Although corticosteroids are potent inhibitors of inflammatory processes, only one study with corticosteroids in patients with postinfectious IBS exists, which suggests that prednisolone is not an effective treatment for IBS symptoms.


OBJECTIVE
To evaluate whether dexamethasone treatment prevents protease-activated receptor-2 (PAR-2) activation-induced visceral hyperalgesia and increased permeability in rats, and to determine whether the effects involve colonic mast cells.


METHODS
Abdominal contractions provoked by rectal distension were recorded in rats equipped with intramuscular electrodes. Changes in visceral hypersensitivity provoked by intracolonic administration of PAR-2-activating peptide (SLIGRL; H-serine-leucine-isoleucine-glycine-arginine-leucine-OH), changes in colonic mucosal rat mast cell protease-II (RMCP-II) content, mast cell count and PAR-2 expression were measured after a 4-day treatment with dexamethasone (1 mg/day/rat intraperitoneally) or its vehicle (water). The effect of mast cell stabiliser (doxantrazole, 1 mg/kg intraperitoneally, 2 h before and 6 h after intracolonic infusion of SLIGRL) on SLIGRL-induced visceral hyperalgesia was also assessed. The effects of SLIGRL and a mast cell degranulator (compound 48/80) on the permeability of colonic strips from vehicle- or dexamethasone-treated rats were investigated in Ussing chambers.


RESULTS
4 days of dexamethasone as well as doxantrazole diminished the SLIGRL-induced hyperalgesia for all volumes of distension. This effect of dexamethasone was accompanied by a reduced responsiveness of colonic permeability to compound 48/80, and decreased RMCP-II content and mast cell number. Dexamethasone treatment did not influence colonic mucosal PAR-2 expression and permeability responsiveness to SLIGRL.


CONCLUSIONS
Dexamethasone treatment improves PAR-2 agonist-induced visceral hypersensitivity but does not prevent PAR-2 agonist-induced increase in colonic permeability in rats. This effect is coupled with a reduction of colonic mast cell number and RMCP-II contents.
Róka
Richard
R
INRA Neuro-Gastroenterology & Nutrition Unit, 180 Chemin de Tournefeuille, BP 3, 31931 Toulouse Cedex 9, France.
Ait-Belgnaoui
Afifa
A
Salvador-Cartier
Christel
C
Garcia-Villar
Raphael
R
Fioramonti
Jean
J
Eutamène
Hélène
H
Bueno
Lionel
L
D000818:Animals; D002452:Cell Count; D003106:Colon / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D003907:Dexamethasone / Q000008:administration & dosage*; D005938:Glucocorticoids / Q000008:administration & dosage*; D006930:Hyperalgesia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D007150:Immunohistochemistry / Q000379:methods; D007263:Infusions, Parenteral; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology; D008666:Metalloendopeptidases / Q000032:analysis; D009842:Oligopeptides / Q000008:administration & dosage; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2 / Q000819:agonists*; D013892:Thioxanthenes / Q000008:administration & dosage; D014781:Viscera / Q000187:drug effects* / Q000503:physiopathology; D044004:Xanthones / Q000008:administration & dosage
D005938:Glucocorticoids; D009842:Oligopeptides; D044464:Receptor, PAR-2; D013892:Thioxanthenes; D044004:Xanthones; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine; D003907:Dexamethasone; D008666:Metalloendopeptidases; C022653:auR protein, Staphylococcus aureus; C010134:doxantrazole