Toxin A from Clostridium difficile mediates acute inflammatory
enterocolitis in experimental animals, while
cholera toxin causes noninflammatory secretory
diarrhea. The purpose of this study was to investigate whether an antagonist to the
peptide substance P, a constituent of primary sensory neurons known to participate in inflammatory responses, would inhibit toxin A-mediated
enteritis in the rat ileum. Pretreatment of rats with CP-96,345 (2.5 mg per kg of
body weight), a
substance P antagonist, dramatically inhibited fluid secretion (P < 0.01) and
mannitol permeability (P < 0.01) in ileal loops exposed to toxin A. The protective effects, which were dose dependent, caused a significant reduction of
inflammation in the lamina propria, reduction of the
necrosis of intestinal epithelial cells, and complete inhibition of toxin A-mediated release of rat mast cell
protease II, a specific product of rat mucosal mast cells. An inactive enantiomer of the
substance P antagonist,
CP-96,344, had no effect. In contrast, pretreatment with CP-96,345 had no inhibitory effect on the intestinal effects caused by administration of
cholera toxin into the ileal loops. From these data, we conclude that the
peptide substance P is involved in the secretory and inflammatory effects of toxin A but not of
cholera toxin.