Pancreatic adenocarcinoma is a fatal malignancy that ranks as the fourth most common cause of cancer-related mortality in the United States. The median survival after diagnosis is 3-6 months, with a 5-year survival rate of 3% or less. In spite of treatment efforts of surgery, radiation, and chemotherapy, the survival rate remains unchanged. In this study, we discovered that an endogenous opioid peptide, [Met5]-enkephalin, inhibited the growth of human pancreatic cancers in vitro; in view of this pentapeptide's action it has been termed opioid growth factor (OGF). OGF was found to be constitutively expressed, autocrine produced, and tonically capable of suppressing cell replication in an opioid receptor mediated manner. Growth inhibition was dose-related, reversible, not cytotoxic, and independent of serum. All 4 pancreatic cancer cell lines examined, representative of poor to well-differentiated neoplasias, exhibited growth regulation by OGF. Immunocytochemical studies detected both OGF and its related receptor, zeta, in the cytoplasm of log phase cells. Radioimmunoassays revealed that OGF was produced and secreted by the cells. These data suggest that a native opioid peptide, OGF, interacts with a novel opioid receptor, zeta, to arrest the growth of human pancreatic cancer.