We investigated the influence of the delta-opioid receptor-preferring agonist D-Ala2-D-Leu2-enkephalin (DADLE) in vitro during long- and short-term hypoxia on the single cortical neuron membrane currents, the postsynaptic currents (PSCs), and the postsynaptic potentials (PSPs) in rats. Rat cortical pyramidal neurons showed 2 distinct and prognostically relevant responses to hypoxia. Type A neurons that responded to hypoxia by an inward current, followed by a steady outward current, were shown to recover during subsequent reoxygenation. In contrast, type B neurons that responded by a steady inward current, indicative of gradual anoxic depolarisation, suffered irreversible membrane dysfunction and did not recover completely during reoxygenation. Pre-treatment with 1 µmol/l DADLE attenuated the hypoxic inward current and favored complete recovery of holding current and input resistance during reoxygenation, even when neurons were challenged by a second exposure to hypoxia. DADLE enhanced the inhibitory effect of hypoxia on PSPs and PSCs. We assume that this neuroprotective effect is transmitted by the additive effects of DADLE on the hypoxic PSP/PSC suppression, thereby inhibiting presynaptic glutamate release.