In patients with unexplained pain after cholecystectomy, morphine often induces pain and may increase plasma aspartate aminotransferase (AST) activity because of exaggerated or prolonged rises in pressure within the biliary system. These anomalous effects of morphine may be mediated by activation of autonomic or related afferent nuclei. In this study, 16 patients with pain and increases in AST after morphine were further studied after pre-treatment with dexamethasone and hydrocortisone. Pre-treatment with dexamethasone decreased scores for pain and nausea and prevented or attenuated increases in plasma AST and glucose; these effects were not observed after pre-treatment with hydrocortisone. Serial changes in plasma concentrations of catecholamines were determined in 8 patients and showed that pre-treatment with dexamethasone, but not hydrocortisone, was associated with lower concentrations of norepinephrine and epinephrine with overall reductions of 53% and 67%, respectively. These observations are consistent with a role for sympatho-adrenomedullary activation in abdominal pain induced by morphine. The different effects of dexamethasone and hydrocortisone raise the possibility that sympatho-adrenomedullary activation after morphine is influenced by the interaction of cortisol with type I glucocorticoid receptors which have a low affinity for dexamethasone and a high affinity for cortisol.