In rat hippocampal slices, high intensity tetanic stimulation (two 1 s trains of 100 Hz separated by 20 s, 3-5X intensity of the test stimulus) of the Schaffer collateral-commissural (SCC) fibers induced a long-term depression (LTD) of the negative field excitatory postsynaptic potentials (fEPSP) in stratum radiatum of the CA1 region. The initial slope of the fEPSP, evoked by a single test shock applied to the SCC fibers, was depressed for a period longer than 40 min following such high intensity tetanic stimulation to this fiber system. However, the same tetanic stimulation delivered at low (test) intensity induced long-term potentiation (LTP) of the fEPSPs. Thus, similar patterns of stimulation can induce either LTP or LTD, depending on whether low- or high-intensity tetanic stimuli are delivered. The LTD induced by high strength tetanic stimulation was clearly blocked by the opioid antagonist naloxone (1 microM); however, the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonopentanoate (AP5; 50 microM) had no effect on the LTD. Our data suggest that the strong stimulation used for LTD induction may have activated other afferent fiber systems and/or local interneurons in addition to SCC fibers, such as the enkephalin-containing terminals of the perforant path (PP) projecting to the stratum lacunosum moleculare or opioid peptide-containing interneurons. Thus, the resulting release of endogenous opioid peptides could play a role in the cellular mechanisms involved in some forms of long-term synaptic depression.