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SUMMARY1. 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. 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.