Enkephalins are naturally occurring peptides with powerful opiate-like effects which have recently been found in nerves of the pancreas. To assess the nature and extent of the influence that opiates exert on the endocrine pancreas, we examined the effects of MET-enkephalin (MEK), leu-enkephalin, morphine, and the opiate antagonist naloxone (NAL) as well as adrenergic and cholinergic blockade on the hormone release from the isolated perfused dog pancreas. It was found that MEK (1-100 nM) dose dependently inhibited somatostatin release and stimulated insulin secretion. The effects of MEK (100 nM) were modulated by the prevailing glucose concentration. Thus, more pronounced changes in D and B cell release were obtained at high (11 mM) rather than at low (1.3 mM) glucose. Ten micromolar of morphine inhibited somatostatin and stimulated insulin secretion, effects being antagonized by NAL (10 microM). NAL (10 microM) similarly counteracted the MEK (50 nM)-induced pertubations in islet hormone secretion. NAL (10 microM) per se did not affect somatostatin or insulin secretion at 8.3 mM glucose. Infusions of either 1 microM phentolamine, 1 microM propranolol, or 1 microM atropine did not significantly alter the amount of somatostatin or insulin secretion during the infusion of 50 nM MEK. In conclusion, the results are suggestive of enkephalins reaching the islets by neural pathways and directly modifying islet hormone secretion by directly interacting with opiate receptors on the islet cells.