Anales RANF

P8. P URINERGIC S IGNALING IN I MMUNOLOGY AND I NFLAMMATION P.74 THE ANTI-INFLAMMATORY AND ANALGESIC EFFECTS OF AR170, A POTENT AND SELECTIVE A 3 RECEPTOR AGONIST, IN A RAT MODEL OF COLITIS L. Antonioli 1 , L. Di Cesare Mannelli 2 , M. Fornai 1 , E. Lucarini 2 , C. Pellegrini 1 , L. Benvenuti 1 , V. D’Antongiovanni 1 , C. Lambertucci 3 , R. Volpini 3 , R. Colucci 4 , C. Ghelardini 2 , C. Blandizzi 1 , D. Dal Ben 3 1 , University of Pisa, Pisa, Italy; 2 University of Florence, Florence, Italy; 3 University of Camerino, Camerino, Italy; 4 University of Padova, Italy. Introduction. The pharmacological activation of adenosine A 3 receptors has shown potential usefulness in the management of bowel inflammation. However, the role of these receptors in the control of visceral hypersensitivity in the presence of intestinal inflammation has not been investigated. Methods. In a first set of experiments, the effects of AR170, a potent and selective A 3 receptor agonist, and dexamethasone (DEX, a standard anti-inflammatory comparator) were tested in male rats (n=6 for each group) with colitis induced by intrarectal administration of 2,4-dinitrobenzenesulfonic acid (DNBS, 30 mg/rat), to assess tissue inflammatory parameters [macroscopic damage, tumor necrosis factor (TNF), interleukin- 1β (IL - 1β), and myeloperoxidase (MPO)] . Animals received AR170 (3 mg/kg/day), DEX (1 mg/kg/day) or vehicle intraperitoneally for 6 days, starting 1 day before the induction of colitis. In a separate set of experiments, visceral pain was assessed by recording somatic motor responses to colo-rectal distension (CRD) in animal with colitis. The effects of AR170 were evaluated after both acute (0.5-4.5 mg/kg i.p.) and repeated (1.5 mg/kg/day i.p.) administration. Results. C olitis was associated with a decrease in body weight, and increase in spleen weight. Macroscopic damage score as well as tissue TNF, IL- 1β and MPO levels were enhanced as well. In the first series of experiments, AR170, but not DEX, improved body weight. Both drugs counteracted the increase in spleen weight, ameliorated the macroscopic colonic damage and decreased TNF, IL- 1β and MPO tissue levels were observed also in rats treated with both test drugs. The second set of experiments displayed an enhanced viscero-motor response to CRD in animals with colitis. Visceral hypersensitivity was decreased by acute administration of AR170 in a dose-dependent fashion, and it was attenuated also with repeated administration of this ligand. The inhibitory effect of AR170 was fully reversed by the selective antagonist MRS1523 (8 mg/kg i.p.). Conclusions. AR170 exerts beneficial effects on bowel inflammation, counteracting inflammatory cell infiltration and decreasing pro-inflammatory cytokine levels. In parallel, the activation of A 3 receptors by AR170 was associated with a significant relief of visceral hypersensitivity under bowel inflammation.