TACHYKININ NK1 AND NK2 RECEPTORS MEDIATE ATROPINE-RESISTANT ILEAL CIRCULAR MUSCLE CONTRACTIONS EVOKED BY CAPSAICIN

The atropine-resistant contractile action of the sensory stimulant dru g capsaicin was examined on guinea-pig ileum circular muscle in vitro, with special regard to the involvement of endogenous tachykinins acti ng through tachykinin NK1 and NK2 receptors. A protocol, using rutheni um red was developed for overcoming desensitization to capsaicin so th at two reproducible responses to this drug were obtained. Capsaicin (1 0(-6) M) caused tonic and phasic contractions of the tissue. This effe ct was significantly inhibited by the tachykinin NK1 receptor blocking drug FK 888 (N-2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol thyl-N-phenylme thyl-3-(-2-naphthyl)-L-alaninamide) or the tachykinin NK2 receptor inh ibitor GR 94,800 (PhCO-Ala-Ala-D.Trp-Phe-D.Pro-Pro-NleNH(2)) (10(-6) M each) and was practically abolished by the combined administration of the two tachykinin receptor blockers. Likewise, the neuronal Na+ chan nel inhibitor tetrodotoxin abolished the response to capsaicin. It is concluded that the contractile effect of capsaicin in the circular mus cle is predominantly mediated by tachykinin release and both subtypes of tachykinin receptor (NK1 and NK2) play an important role in this pr ocess. The source of tachykinins, however, is probably intrinsic neuro ns of the myenteric plexus, indirectly activated by capsaicin-sensitiv e nerves, as shown by the sensitivity of the response to tetrodotoxin.