By use of the opiate antagonist naloxone, we have examined the hormonal and metabolic responses to opiate-receptor blockade under basal conditions and during insulin-induced hypoglycemia in normal dogs. Naloxone treatment had no measurable effect on glucose concentration, turnover, and norepinephrine levels, but stimulated plasma epinephrine, glucagon, and cortisol and inhibited insulin release. Insulin (7 mU X kg-1 X min-1) decreased plasma glucose to 42 +/- 4 mg/dl due to an initial decrease in glucose production and an increase in glucose disappearance. Glucose production then increased, and plasma glucose plateaued. After 50 min of insulin infusion, epinephrine levels increased 26-fold (P less than 0.05), norepinephrine and glucagon 3-fold (P less than 0.02), and cortisol 4-fold (P less than 0.01). Similarly, plasma beta-endorphin and adrenocorticotropin (ACTH) were elevated (6-fold, P less than 0.01, and 16-fold, P less than 0.05, respectively). When naloxone was given during insulin-induced hypoglycemia, there was earlier release of epinephrine, glucagon, beta-endorphin, ACTH, and cortisol as well as a greater release of glucagon (P less than 0.001) and cortisol (P less than 0.0001). This resulted in a greater increase in glucose production (P less than 0.01), thus lessening the insulin-induced hypoglycemic excursion. In conclusion, in the dog, endogenous opiates may play a small role in the regulation of basal insulin and glucagon release and can inhibit the pituitary-adrenal axis under basal conditions and during hypoglycemia. Thus increased glucose production in response to insulin-induced hypoglycemia is consistent with the excessive response of counterregulatory hormones during opiate-receptor blockade.