Administration of synthetic human corticotropin-releasing factor (hCRF, 2 micrograms/kg body weight) to 6 normal men produced a significant rise in plasma pancreatic polypeptide (PP) levels. This PP-stimulating effect of hCRF could not be observed in 6 male Type 2 diabetic patients. Simultaneous application of the opioid antagonist naloxone (1.6 mg i.v. bolus, followed by an infusion at a rate of 1.2 mg/h) led to a restoration of the normal PP response to hCRF in the diabetic patients, while in normal subjects, during this combined treatment, the hCRF-induced PP peak occurred somewhat delayed. Our results provide further evidence for a role of hCRF as a stimulatory factor of PP release in normal men. Moreover, it is suggested that endogenous opioids may be part of a modulatory principle co-regulating the secretion of PP. An elevated tone of such an opioidergic PP control system could be responsible for the impaired PP response to hCRF in Type 2 diabetics.