The relaxant effect of capsaicin was investigated on isolated segments of guinea pig ileum precontracted by histamine. Two types of relaxation could be distinguished. Low concentrations of capsaicin (0.033-3.3 microM) caused partial relaxation (type I) which was prevented by in vitro desensitization to capsaicin or by extrinsic denervation and reduced by tachyphylaxis to calcitonin gene-related peptide. At higher concentrations (10-100 microM) capsaicin caused relaxation (type II) to the baseline; this effect was insensitive to capsaicin desensitization or extrinsic denervation. Neither type of relaxation was inhibited by tetrodotoxin or by alpha- and beta-adrenoceptor antagonists. We suggest that type I relaxation results from a specific effect of capsaicin on extrinsic sensory neurones of the gut while type II represents a non-specific smooth muscle depressant effect. Intrinsic enteric neurones are not involved in these effects.