The role of platelet-activating factor (PAF) and substance P in stimulating abnormal motor activity during ileal inflammation was investigated in conscious dogs. All test substances were infused close-i.a. in short segments of the ileum. Ileal inflammation was induced by mucosal exposure to a series of ethanol and acetic acid infusions. In the normal state, PAF stimulated phasic contractions and some giant migrating contractions (GMCs), whereas substance P stimulated only phasic contractions. During inflammation, PAF stimulated a significantly greater number of GMCs, but there was no significant difference in the area under phasic contractions between the normal and inflamed states. Atropine, tetrodotoxin, hexamethonium, verapamil, diltiazem, and dantrolene significantly inhibited the response to PAF in both the normal and the inflamed state. By contrast, inhibition of nitric oxide by N omega-nitro-L-arginine methyl ester enhanced the contractile response to PAF. N-(6-ammohexyl)-5-chloro-1-naphtalenesulfonamide hydrochloride, a calmodulin antagonist, did not affect the response to PAF. Methacholine, neostigmine and motilin stimulated only phasic contractions during the normal state, but they stimulated both phasic contractions and GMCs during the inflamed state. We conclude that PAF is one of the inflammatory response mediators that may stimulate GMCs during ileal inflammation. The inflammatory response may modulate the enteric neuronal and cellular control of contractions such that the cholinergic mechanisms of stimulation of GMCs are sensitized during inflammation.