Microinjections of 1-20 μg of leu-enkephalin were done in the dorsal hippocampus of cats and rats in acute experiments. Long lasting epileptiform changes in the hippocampal EEG were produced. These changes were prevented by previous microinjections of naloxone at the same site. When repeated microinjections of the same dose of enkephalin which initially was epileptogenic were done a progressive loss of effectiveness of the drug was observed. Also, progressively higher doses of enkephalin were necessary to produce effects comparable to the effect of the initial injection. These results suggest that acute tolerance may develop to the epileptogenic effect of leu-enkephalin in hippocampus.