DOR activation inhibits anoxic/ischemic Na+ influx through Na+ channels via PKC mechanisms in the cortex

Activation of delta-opioid receptors (DOR) is neuroprotective against hypoxic/ischemic injury in the cortex, which is at least partially related to its action against hypoxic/ischemic disruption of ionic homeostasis that triggers neuronal injury. Na + influx through TTX-sensitive voltage-gated Na + channels may be a main mechanism for hypoxia-induced disruption of K + homeostasis, with DOR activation attenuating the disruption of ionic homeostasis by targeting voltage-gated Na + channels. In the present study we examined the role of DOR in the regulation of Na + influx in anoxia and simulated ischemia (oxygen-glucose deprivation) as well as the effect of DOR activation on the Na + influx induced by a Na + channel opener without anoxic/ischemic stress and explored a potential PKC mechanism underlying the DOR action. We directly measured extracellular Na + activity in mouse cortical slices with Na + selective electrodes and found that (1) anoxia-induced Na + influx occurred mainly through TTX-sensitive Na + channels; (2) DOR activation inhibited the anoxia/ischemia-induced Na + influx; (3) veratridine, a Na + channel opener, enhanced the anoxia-induced Na + influx; this could be attenuated by DOR activation; (4) DOR activation did not reduce the anoxia-induced Na + influx in the presence of chelerythrine, a broad-spectrum PKC blocker; and (5) DOR effects were blocked by PKCβII peptide inhibitor, and PKCθ pseudosubstrate inhibitor, respectively. We conclude that DOR activation inhibits anoxia-induced Na + influx through Na + channels via PKC (especially PKCβII and PKCθ isoforms) dependent mechanisms in the cortex.