This work evaluates the mechanism of action of calcitonin gene-related peptide (CGRP) on colitis. Firstly, Wistar rats were intracolonically instilled with trinitrobenzenesulfonic acid (TNBS) and i.v. treated by either alphaCGRP, or hCGRP(8-37), or by vehicle. The inflammatory level was evaluated 8 h and 4 days after TNBS. Secondly, intracerebroventricular alphaCGRP was assessed on the 4-day group with colitis. Finally, i.v. alphaCGRP was administered in vagotomized animals, and tested on the 4-day group with colitis. Colitis was aggravated by hCGRP(8-37), and decreased by peripheral but not central alphaCGRP. AlphaCGRP was inactive on inflammatory parameters in vagotomized colitic rats. This suggests that endogenous peripheral CGRP has an anti-inflammatory role in TNBS-induced colitis, depending upon the integrity of the vagus.