We examined the effects of substance P (SP) on the myoelectric activity of the opossum sphincter of Oddi (SO). Myoelectric data from the SO in five adult opossums were recorded using thin stainless steel electrodes and computer-assisted analog-to-digital conversion. In fully awake and conscious animals, baseline spikeburst activity during phase I of the MMC occurred at a frequency of 28.6 +/- 3.1 spikebursts (SB) per 20-min period. Intravenous infusion of graded doses of substance P (from 0.5 to 8.0 micrograms/kg) stimulated SO myoelectric activity in a dose-related manner (from 80 +/- 8 to 235 +/- 11 SB/20 min, respectively, P less than 0.05 when compared to baseline). The effect of substance P on SO myoelectric activity was antagonized by administration of the H2-blocker, cimetidine (92.0 +/- 6.1 vs 48.2 +/- 7.0, n = 5, P less than 0.05). Administration of the antimuscarinic drug atropine only slightly affected the SO spikeburst frequency when infused prior to SP (73.0 +/- 10.4 vs 70.8 +/- 8.2, P greater than 0.05). We conclude that SP stimulated the SO spikeburst frequency in a dose-dependent fashion. Cimetidine markedly inhibited the response of the SO to SP but atropine did not. The excitatory effect of substance P on the opossum SO is mediated at least in part by a histaminergic, noncholinergic pathway.