The effect of thiorphan, an inhibitor of enkephalin dipeptidyl carboxypeptidase, was tested in the rat tail-flick test. When given alone up to 100 mg/kg s.c., thiorphan had no effect. However, thiorphan (30 mg/kg, s.c.) potentiated intraventricularly administered [D-Ala2,Met5]enkephalinamide (DEAEM) and its [Leu5]-derivative, whereas it had no effect on [D-Ala2,Met5]enkephalin, [D-Met2,Pro5]enkephalinamide, or morphine. Potentiation of DAEAM by thiorphan was dose-responsive and naloxone reversible. The most efficient enhancement of the analgesic effects of DAEAM was seen when the two drugs were co-administrated in rapid succession. Thus, thiorphan potentiation of opioid-peptide induced analgesia in the rat is similar to that seen in the mouse.