BACKGROUND: The neurotransmitter substance P (SP) released by, and the transient receptor potential vanilloid (TRPV1), expressed by afferent nerves, have been implicated in mucosal neuro-immune-regulation. To test if enteric afferent nerves are of importance for the development of chronic colitis, we examined antagonists for the high-affinity neurokinin 1 (NK-1) SP receptor and the TRPV1 receptor agonist capsaicin in a T-cell transfer model for chronic colitis. METHODS: Chronic colitis was induced in SCID mice by injection of CD4(+)CD25(-) T cells. The importance of NK-1 signaling and TRPV1 expressing afferent nerves for disease development was studied in recipient SCID mice systemically treated with either high-affinity NK-1 receptor antagonists or neurotoxic doses of capsaicin. In addition, we studied the colitis-inducing effect of NK-1 receptor deleted CD4(+)CD25(-) T cells. RESULTS: Treatment with the NK-1 receptor antagonist CAM 4092 reduced the severity of colitis, but colitis was induced by NK-1 receptor-deleted T cells, suggesting that SP in colitis targets the recipient mouse cells and not the colitogenic donor T cells. Capsaicin-induced depletion of nociceptive afferent nerves prior to CD4(+)CD25(-) T-cell transfer completely inhibited the development of colitis. CONCLUSIONS: Our data demonstrate the importance of an intact enteric afferent nerve system and NK-1 signaling in mucosal inflammation and may suggest new treatment modalities for patients suffering from inflammatory bowel disease.