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.
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