It has been shown previously that both forms of interleukin-1, 1α and 1β, produce dose-dependent relaxation of the rat gastric fundus in vitro, accompanied by an increased production and release of eicosanoids. This effect appears to be mediated, at least in part, by leukotrienes, since the inhibition of 5-lipoxygenase by specific drugs counteracts interleukin-1-induced gastric relaxation. In the present study, we attempted to antagonize interleukin-1-induced inhibition of gastric fundus motility with a interleukin-1 receptor antagonist. Surprisingly, the interleukin-1 receptor antagonist itself possessed interleukin-1-like agonist activity, since: (a) it produced rapid, dose-dependent relaxation of the rat gastric fundus, with an estimated EC 5 0 of 70 pg/ml and a maximal effect at 10 ng/ml; (b) interleukin-1 receptor antagonist-induced relaxation was dose dependently inhibited byN -(3-phenoxycinnamyl)acetohydroxamic acid (BW A4c), a specific inhibitor of 5-lipoxygenase; (c) in the first 5 min after its addition to the bath solution, interleukin-1 receptor antagonist produced a significant increase in prostaglandin E 2 release from the gastric strips. This evidence suggests that, shortly after receptor occupancy, in this experimental model interleukin-1 and interleukin-1 receptor antagonist share the same pattern of mechanical and biochemical activities.