We have recently found that in the mouse cortex, activation of delta-opioid receptor (DOR) attenuates the disruption of K(+) homeostasis induced by hypoxia or oxygen-glucose deprivation. This novel observation suggests that DOR may protect neurons from hypoxic/ischemic insults via the regulation of K(+) homeostasis because the disruption of K(+) homeostasis plays a critical role in neuronal injury under hypoxic/ischemic stress. The present study was performed to explore the ionic mechanism underlying the DOR-induced neuroprotection. Because anoxia causes Na(+) influx and thus stimulates K(+) leakage, we investigated whether DOR protects the cortex from anoxic K(+) derangement by targeting the Na(+)-based K(+) leakage. By using K(+)-sensitive microelectrodes in mouse cortical slices, we showed that 1) lowering Na(+) concentration and substituting with impermeable N-methyl-D-glucamine caused a concentration-dependent attenuation of anoxic K(+) derangement; 2) lowering Na(+) concentration by substituting with permeable Li(+) tended to potentiate the anoxic K(+) derangement; and 3) the DOR-induced protection against the anoxic K(+) responses was largely abolished by low-Na(+) perfusion irrespective of the substituted cation. We conclude that external Na(+) concentration greatly influences anoxic K(+) derangement and that DOR activation likely attenuates anoxic K(+) derangement induced by the Na(+)-activated mechanisms in the cortex.