The effects of morphine on intraluminal pressures recorded from the sphincter of Oddi (SO) at endoscopic retrograde cholangiopancreatography in 19 patients who were without evidence of biliary or pancreatic disease were studied. Morphine was given in four successive doses of 2.5, 2.5, 5, and 10 μg/kg iv at five minute intervals. Morphine in subanalgesic doses increased the frequency of SO phasic pressure waves to a maximum of 10-12/min, caused the phasic waves to occur simultaneously along the sphincter segment, increased phasic wave amplitude from 72 (26) (SE) to 136 (31) mmHg, and increased SO basal pressure from 10 (1) to 29 (9) mmHg (p < 0.05). The effects of morphine on the SO are mediated by more than one opioid receptor type, as naloxone competitively antagonised the increase in phasic wave frequency induced by morphine, but did not affect the increase in SO basal pressure elicited by morphine. When given after naloxone, morphine decreased phasic wave amplitude, an inhibitory effect that is normally masked by morphine's dominant naloxone sensitive excitatory effect. Mu receptors do not appear to be involved in control of spontaneous SO motor function, as naloxone alone did not affect SO motor activity. The excitatory effects of morphine on the SO are not mediated by cholinergic nerves, as they were not blocked by atropine. Cholinergic nerves, however, may have a role in regulating spontaneous SO motor function because atrophine alone depressed phasic wave activity and basal pressure. Although morphine does cause 'spasm' of the human SO, its effects are more complex than is commonly believed.