The effects of selective agonists and antagonists of opioid receptors on the secretion of corticotrophin releasing factor (CRF) by isolated rat hypothalami in vitro were studied. Morphine (10(-8)-10(-6) M) and the mu-opioid receptor agonists, FK33-824CH (10(-8)-10(-6) M) and Tyr-D-Ala-Gly-MePhe-NH(CH2)2OH (10(-8)-10(-6) M), caused dose-related increases in the release of CRF from isolated hypothalami. The kappa-opioid receptor agonist, U50,488 (10(-8)-10(-6) M), was also weakly active in this respect but the delta-opioid receptor agonist, (D-Pen2,D-Pen5)-enkephalin (2 X 10(-10)-2 X 10(-7) M), was not. The stimulatory actions of morphine and Tyr-D-Ala-Gly-MePhe-NH(CH2)2OH on CRF release were antagonized by naloxone (10(-8) M) and by the mu/delta-opioid receptor antagonist, beta-funaltrexamine (beta-FNA, 10(-9) M), but not by the delta-opioid receptor antagonist, ICI-154129 (5 X 10(-6) M). The effects of U50,488 on CRF release were unaffected by either beta-FNA or ICI-154129 but were antagonized by high doses of naloxone (10(-6) M). The results suggest that both mu- and kappa-opioid receptors are involved in the stimulation of CRF secretion but that delta-opioid receptors are not important in this respect.