The atropine-resistant contractile action of the sensory stimulant drug capsaicin was examined on guinea-pig ileum circular muscle in vitro, with special regard to the involvement of endogenous tachykinins acting through tachykinin NK1 and NK2 receptors. A protocol, using ruthenium red was developed for overcoming desensitization to capsaicin so that two reproducible responses to this drug were obtained. Capsaicin (10(-6) M) caused tonic and phasic contractions of the tissue. This effect was significantly inhibited by the tachykinin NK1 receptor blocking drug FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-proly]-N- methyl-N-phenylmethyl-3-(-2-naphthyl)-L-alaninamide) or the tachykinin NK2 receptor inhibitor GR 94,800 (PhCO-Ala-Ala-D.Trp-Phe-D.Pro-Pro-NleNH2) (10(-6) M each) and was practically abolished by the combined administration of the two tachykinin receptor blockers. Likewise, the neuronal Na+ channel inhibitor tetrodotoxin abolished the response to capsaicin. It is concluded that the contractile effect of capsaicin in the circular muscle is predominantly mediated by tachykinin release and both subtypes of tachykinin receptor (NK1 and NK2) play an important role in this process. The source of tachykinins, however, is probably intrinsic neurons of the myenteric plexus, indirectly activated by capsaicin-sensitive nerves, as shown by the sensitivity of the response to tetrodotoxin.