Evidence that the contractile response of the guinea-pig ileum to capsaicin is due to release of substance P.

1. The possible roles of substance P and opioids in the contractile response of the isolated guinea-pig ileum to the sensory stimulant drug capsaicin were investigated, and the contractions were found to be inhibited by about 60% in preparations desensitized to substance P. 2. Contractions evoked by stimulation of the mesenteric nerves in the presence of the adrenergic blocking drug guanethidine were inhibited by about 75% after the ileum had been rendered insensitive to substance P. 3. Atropine partially inhibited the effect of capsaicin. The atropine-resistant component of the contractile response to capsaicin was inhibited by more than 85% in preparations desensitized to substance P and almost abolished by the substance P antagonist, (D-Pro2,D-Trp7,9)-substance P. 4. The opioid peptide (D-Met2, Pro5)-enkephalinamide inhibited, whereas the opiate antagonist naloxone enhanced the atropine-resistant contractions in response to capsaicin. 5. The results indicate that the contractile response of the guinea-pig ileum to capsaicin and mesenteric nerve stimulation is mediated by release of substance P, presumably from sensory nerve endings in the gut. Substance P appears to act on the smooth muscle both directly and indirectly via cholinergic neurones. It is proposed that opioids modulate the non-cholinergic response to capsaicin by inhibiting the release of substance P.