Morphine has been extensively used in the treatment of pulmonary edema, and its action is believed to be mediated in part by its ability to produce peripheral venodilation. This study investigated whether opiates produce venodilation in human hand veins and explored the underlying mechanism(s). Fifteen healthy volunteers (11 men and four women) were studied with use of the dorsal hand vein compliance technique. After preconstriction with the selective alpha 1-adrenergic receptor agonist phenylephrine, dose-response curves were constructed to (1) opiate receptor agonists morphine (1 to 30 micrograms/min) or fentanyl (0.07 to 1 microgram/min), (2) a combination of morphine and the mu-opiate receptor antagonist naloxone, and (3) morphine and a combination of histamine (H1 and H2) receptor antagonists. Infusion of morphine caused venodilation in a dose-dependent manner, whereas fentanyl did not produce venodilation. Coinfusion of naloxone and morphine impaired the venodilation only slightly. Coinfusion of the H1- and H2-antagonists completely abolished the venodilatory effect of morphine. These results suggest that the venodilatory effect of morphine is mediated through histamine release and that mu-opiate receptors have little or no involvement in this process.