Ileal pouch-anal anastomosis (IPAA) is an excellent surgical option for patients with chronic ulcerative colitis (CUC) requiring colectomy; however, persistent episodes of ileal pouch inflammation or pouchitis may result in debilitating postoperative complications. Since considerable evidence implicates substance P (SP) as an inflammatory mediator of CUC, we investigated whether SP participates in the pathophysiology of pouchitis. Using a rat model of IPAA that we developed, we showed that ileal pouch myeloperoxidase (MPO) levels and neurokinin 1 receptor (NK-1R) protein expression by Western blot analysis were significantly elevated 28 days after IPAA surgery. In situ hybridization and immunohistochemistry showed that the increase in NK-1R protein expression was localized to the lamina propria and epithelia of pouch ileum. The intraperitoneal administration of the neurokinin 1 receptor antagonist (NK-1RA), CJ-12,255 for 4 days, starting on day 28, was effective in reducing MPO levels. Starting on day 28, animals with IPAA were given 5% dextran sulfate sodium (DSS) in their drinking water for 4 days, which caused histological and physical signs of clinical pouchitis concomitant with significant increases in ileal pouch MPO concentrations as well as NK-1R protein expression by Western blot analysis. In situ hybridization and immunohistochemistry showed that the increase in NK-1R protein expression was especially to crypt epithelia of pouch ileum. When the NK-1RA was administered 1 day before starting DSS, and continued for the duration of DSS administration, the physical signs of clinical pouchitis, and the rise in MPO were prevented. These data implicate SP in the pathophysiology of pouchitis, and suggest that NK-1RA may be of therapeutic value in the management of clinical pouchitis.