5-Amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester (ATB-429), a hydrogen sulfide-releasing derivative of mesalamine, exerts antinociceptive effects in a model of postinflammatory hypersensitivity.
H(2)S functions as a neuromodulator and exerts anti-inflammatory activities. Recent data indicate that irritable bowel syndrome (IBS) is linked to inflammation of the gastrointestinal tract. In this study, we have investigated the role of a novel H(2)S-releasing derivative of mesalamine (5-amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester, ATB-429) in modulating nociception to colorectal distension (CRD), a model that mimics some features of IBS, in healthy and postcolitic rats. Four graded (0.4-1.6 ml of water) CRDs were produced in conscious rats, and colorectal sensitivity and pain were assessed by measuring the abdominal withdrawal response and spinal c-Fos expression. In healthy rats, ATB-429 dose dependently (25, 50, or 100 mg/kg) attenuated CRD-induced hypersensitivity and significantly inhibited CRD-induced overexpression of spinal c-FOS mRNA, whereas mesalamine had no effect. ATB-429-induced antinociception was reversed by glibenclamide, a ATP-sensitive K(+) (K(ATP)) channel inhibitor. The antinociceptive effect of ATB-429 was maintained in a rodent model of postinflammatory hypersensitivity (4 weeks after colitis induction). At a dose of 100 mg/kg, ATB-429 reversed the allodynic response caused by CRD in postcolitic rats. Colonic cyclooxygenase-2 and interkeukin-1beta mRNA and spinal c-FOS mRNA expression were significantly down-regulated by ATB-429, but not by mesalamine. ATB-429, but not mesalamine, increased blood concentrations of H(2)S in both healthy and postcolitic rats. Taken together, these data suggest that ATB-429 inhibits hypersensitivity induced by CRD in both healthy and postcolitic, allodynic rats by a K(ATP) channel-mediated mechanism. This study provides evidence that H(2)S-releasing drugs might have beneficial effects in the treatment of painful intestinal disorders.
Distrutti
Eleonora
E
Clinica di Gastroenterologia, Policlinico Monteluce, University of Perugia, Via Enrico Dal Pozzo, 06122 Perugia, Italy. eleonoradistrutti@katamail.com
Sediari
Luca
L
Mencarelli
Andrea
A
Renga
Barbara
B
Orlandi
Stefano
S
Russo
Giuseppe
G
Caliendo
Giuseppe
G
Santagada
Vincenzo
V
Cirino
Giuseppe
G
Wallace
John L
JL
Fiorucci
Stefano
S
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D004220:Disulfides / Q000493:pharmacokinetics / Q000494:pharmacology*; D006862:Hydrogen Sulfide / Q000378:metabolism*; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D008297:Male; D019804:Mesalamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000378:metabolism
C514446:5-amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-(1,2)dithiol-3yl)phenyl ester; D000700:Analgesics; D004220:Disulfides; D026902:Potassium Channel Blockers; D019804:Mesalamine; D006862:Hydrogen Sulfide