We investigated the possibility that substance P would mediate defecation in rats subjected to restraint-stress. The increases in fecal pellet output caused by restraint-stress were inhibited by a neurokinin (NK)1 receptor antagonist, RP67580 with an ED50 (95% confidence limits) value of 0.59 (0.54-0.65) mg/kg i.p. RP68651, the enantiomer of RP67580 devoid of affinity for NK1 receptors, had little effect on it. In contrast, (+/-)SR48968, an NK2 receptor antagonist, was without effect. Furthermore, capsaicin treatment (125 mg/kg i.p.) was inactive in this model. These results suggest that the activation of NK1 receptors and substance P released from intrinsic neurons of the colon would be involved in stress-induced defecation in rats.