The effect of morphine on esophageal motility has been little explored. In eight healthy volunteers, we studied the effect of intravenous morphine (100 micrograms/kg) followed 60 min later by intravenous naloxone (80 micrograms/kg) and of intravenous naloxone alone (80 micrograms/kg) on the esophageal motor response to swallowing and 30-s intraluminal distensions(4, 6, 8, and 10 ml) during two separate experiments. Morphine increased (P < 0.01) the velocity but did not alter the amplitude or duration of primary peristalsis, and it decreased the duration and magnitude of swallow-induced lower esophageal sphincter (LES) relaxation (P < 0.01). It also markedly increased contractile activity below the balloon at high distending volumes (P < 0.05) and decreased the magnitude of distension-induced LES relaxation (P < 0.05) but did not affect contractile activity above the balloon. All effects were reversed by naloxone. The latter alone did not influence the esophageal response to swallowing or distension. The conclusions are that 1) morphine exerts effects on the response of the human esophagus to swallowing and intraluminal distension that are consistent with an action at the level of the inhibitory neural pathways, 2) these effects occur through opioid receptors, and 3) endogenous opioids do not seem to control esophageal motility, at least through mu-receptors.