Purpose: Primary sensory neurons are important in the initiation and propagation of intestinal inflammation. The vanilloid receptor subtype-1 (VR-1) is a recently discovered cation channel found on sensory nerves which, when stimulated, releases pro-inflammatory peptides such as substance P. Previous reports have shown that inhibition of VR-1 with capsazepine (CPZ), a VR-1 antagonist, attenuates dextran sodium sulfate (DSS) colitis in rats. DSS-induced colitis resembles ulcerative colitis in its pathologic features. In this study, we examined the effect of CPZ on trinitrobenzene sulfonic acid (TNBS)-induced colitis, an experimental model of intestinal inflammation that most closely resembles the histologic and microscopic features of Crohn's disease. Methods: Colitis was induced by administering a single enema of 100 mg/kg TNBS in 50% ethanol via catheter to lightly anesthetized rats. Subsets of rats were treated with either 1 μmole/kg/ml of CPZ or CPZ vehicle via enema for six days. Seven days following TNBS administration, rats were sacrificed and inflammation was assessed using a validated macroscopic damage score (MDS), and myeloperoxidase (MPO) activity. Qualitative histology was also performed. Results: TNBS administration resulted in reproducible chronic erosive lesions extending into the muscularis propria and extensive recruitment of neutrophils in the distal colon. MDS and MPO scores were significantly elevated in the TNBS colons when compared to the CPZ-vehicle animals (Table 1). TNBS rats treated with CPZ enemas had a significant reduction in MDS and MPO scores, and demonstrated dramatically improved pathologic findings. Conclusions: Topical CPZ, a VR-1 antagonist, resulted in significant attenuation of TNBS-induced colitis. These results support the role of VR-1 and sensory neurons in intestinal inflammation.