There is good evidence indicating that hyoscine-resistant contractions of the guinea-pig ileum evoked by stimulation of the intramural nerves are mediated by substance P (SP). In the present experiments, non-cholinergic neurogenic ileum contractions to field stimulation (100 imp., 5-50 Hz) were inhibited by the opiate agonists morphine and [D-Met2,Pro5]enkephalinamide (10(-6) M) in a naloxone-reversible manner. Neither morphine nor naloxone influenced the musculodirect contracting effect of histamine. Capsaicin, a drug that has been shown to deplete SP from primary afferent neurones, exerted no long-lasting effect on non-cholinergic contractions to field stimulation. Repeated administration of long trains of stimuli (900 impulses) resulted in a progressive decrease of the contractions evoked. Addition of naloxone (3 X 10(-7) M) restored the original height of the responses. The above inhibitory action of opiate agonists and of repeated long-train stimulation was 3-6 times greater at 5 Hz than at 50 Hz. It is concluded that opiate agonists inhibit the release of SP from intramural neurones of the guinea-pit ileum. The decrease in responses to repeated long-train stimulations is mediated, at least in part, by the release of endogenous opioid substance(s).