SR140333, a substance P receptor antagonist, influences morphological and motor changes in rat experimental colitis

The etiology of inflammation, edema, and smooth muscle contraction characte ristic of inflammatory bowel disease is not clearly understood. There is ev idence that several neuropeptides, including substance P (SP), may play a r ole. In this study we evaluated the ability of a SP-antagonist (SR140333) t o modify the course of experimental colitis induced in the rat by trinitrob enzene sulfonic acid (TNB). Colitis was induced in 24 rats using TNB applie d by intrarectal enema. Twelve TNB-treated rats received SR140333, 0.1 mg/k g intraperitoneally, 30 min before the administration of TNB and every 48 h r until death. Twelve rats receiving only intrarectal 0.9% saline served as controls. Rats of each group were killed after 14 days. At day 14, the con trol group showed no signs of inflammation whereas the TNB-treated rats wit hout SR140333 treatment exhibited a well-established colitis. The TNB-treat ed group had a higher level of inflammation, as seen histologically and by the significantly greater weight of colon strips, compared to the controls (0.30 +/- 0.09 g vs 0.13 +/- 0.03 g, P < 0.001) and to the SR140333-treated rats (0.30 +/- 0.09 g vs 0.14 +/- 0.05 g, P ( 0.001). In addition, smooth muscle contractility was significantly reduced in the inflamed colons of TN B-treated rats when compared with the controls (carbachol: 42.7 +/- 20.3 vs 254.2 +/- 69.78 mg/mm(2); SP: 18.5 +/- 10.02 vs 89.45 +/- 23.17 mg/mm(2); KCl: 11.4 +/- 2.2 vs 98.32 +/- 33.57 mg/mm(2), P < 0.01). However, SR140333 -treated rats showed a recovery from inflammation and motor alterations cau sed by TNB (carbachol: 150.9 +/- 46.1 mg/mm(2), P < 0.01; SP: 32.5 +/- 9.4 mg/mm(2), P < 0.05; KCl: 125.7 +/- 36.1 mg/mm(2), P < 0.01). In conclusion, treatment with SP antagonist SR140333 reduces the severity of colitis and has beneficial effects on the concomitant alterations of contractility. Thu s, the blockade of substance P may represent a possibility in the treatment of intestinal inflammation.