Neuropeptides liberated from enteric neurons have been suggested to contribute to the inflammatory process in colitis. Based in part on this evidence, lidocaine enemas have recently been suggested as a treatment for ulcerative colitis, but their effects have yet to be fully characterized. We have assessed the effects of lidocaine on the development and maintenance of colitis induced by trinitrobenzenesulfonic acid (TNBS) in rats. In the initial experiments, rats were given lidocaine [5-100 mg/kg intrarectally] 30 min before TNBS administration, and the severity of colitis was assessed 6-24 h later. In subsequent experiments, rats received lidocaine intrarectally or subcutaneously 30 min before TNBS administration and once daily for 7 days. The severity of colitis was assessed by blind macroscopic scoring, measurement of myeloperoxidase activity, and histological evaluation. Lidocaine dose dependently reduced the severity of colitis and the infiltration of granulocytes at 24 h and 7 days post-TNBS. At the latter time point, lidocaine was also found to improve the histological appearance of the tissue and significantly reduce mucosal mast cell hyperplasia. Beneficial effects were also evident when intrarectal lidocaine treatment was initiated after induction of colitis or when lidocaine was given subcutaneously. Granulocyte infiltration into the colon could also be attenuated by a substance P receptor antagonist. These results suggest that lidocaine can exert anti-inflammatory effects in colitis, perhaps by virtue of its effects on intrinsic and/or extrinsic nerves.