The influence of opioid antagonists and of morphine on rat hippocampal slices in a model of reversible hypoxia/hypoglycemia was investigated by assessment of evoked field potentials (population spike amplitude). In control slices, a brief hypoxia/hypoglycemia led to a loss of field potentials followed by an impaired recovery (40–50% of baseline) during reperfusion. In contrast, restoration was significantly improved when the opioid receptor antagonists funaltrexamine (μ) or naltrindole (δ) were administered prior to and during hypoxia/hypoglycemia. In addition, recovery was improved in brain slices derived from μ-opioid receptor-deficient mice as compared to wild-type mice, indicating a deleterious role of endogenous opioids in hypoxia/hypoglycemia. Exogenous opiate exposure with morphine (0.1, 1.0, 10 μM) prior to hypoxia/hypoglycemia caused a slight concentration dependent increase of evoked field potentials. When morphine exposure was terminated after 1 h and immediately followed by hypoxia/hypoglycemia, an impaired recovery of population spike amplitude was obtained, dependent on morphine concentration during preincubation. These results demonstrate that morphine aggravates neurotoxic effects of hypoxia/hypoglycemia. Conversely, when onset of hypoxia/hypoglycemia was delayed for 3 h after morphine termination, a significantly improved recovery was observed. Similarly, in vivo administration of morphine 12 h prior to slice preparation resulted in a dose dependent improved recovery of field potentials after hypoxia/hypoglycemia. These results provide evidence that preconditioning with morphine is able to induce neuroprotective effects.