We previously reported that delta-9-tetrahydrocannabinol (delta-9-THC), the primary psychoactive constituent of Cannabis sativa, inhibited gastric motor activity and evoked bradycardia and hypotension upon its parenteral administration in the rat. As prostanoids are important mediators of the actions of cannabinoids, we hypothesized that the inhibitory gastric motor and cardiovascular effects of delta-9-THC could depend on cyclooxygenase (COX) activation in the hindbrain and/or in the periphery. To test this hypothesis, vehicle or delta-9-THC (0.2 mg/kg, i.v.) were administered before and 15-min after the COX inhibitor tolmetin (50 mg/kg, i.v.) or 15 min after topical application of tolmetin to the surface of the dorsal medulla (0.5 mg/rat) in chloralose-anesthetized rats. Delta-9-THC-evoked gastric motor inhibition and bradycardia were abolished by parenteral and were attenuated by hindbrain administration of tolmetin. Moreover, administration of delta-9-THC after parenteral tolmetin evoked marked and long-lasting hypertension. We concluded that the inhibitory gastric motor and cardiovascular effects of systemically administered delta-9-THC depend on the hindbrain and peripheral activation of COX.