δ‐, but not µ‐, opioid receptor stabilizes K + homeostasis by reducing Ca 2+ influx in the cortex during acute hypoxia

Past work has shown that δ‐opioid receptor (DOR) activation by [D‐Ala 2 ,D‐Leu 5 ]‐enkephalin (DADLE) attenuated the disruption of K + homeostasis induced by hypoxia or oxygen‐glucose deprivation (OGD) in the cortex, while naltrindole, a DOR antagonist blocked this effect, suggesting that DOR activity stabilizes K + homeostasis in the cortex during hypoxic/ischemic stress. However, several important issues remain unclear regarding this new observation, especially the difference between DOR and other opioid receptors in the stabilization of K + homeostasis and the underlying mechanism. In this study, we asked whether DOR is different from µ‐opioid receptors (MOR) in stabilizing K + homeostasis and which membrane channel(s) is critically involved in the DOR effect. The main findings are that (1) similar to DADLE (10 µM), H‐Dmt‐Tic‐NH‐CH (CH 2 COOH)‐Bid (1–10 µM), a more specific and potent DOR agonist significantly attenuated anoxic K + derangement in cortical slice; (2) [D‐Ala 2 , N‐Me‐Phe 4 , glycinol 5 ]‐enkephalin (DAGO; 10 µM), a MOR agonist, did not produce any appreciable change in anoxic disruption of K + homeostasis; (3) absence of Ca 2+ greatly attenuated anoxic K + derangement; (4) inhibition of Ca 2+ ‐activated K + (BK) channels with paxilline (10 µM) reduced anoxic K + derangement; (5) DADLE (10 µM) could not further reduce anoxic K + derangement in the Ca 2+ ‐free perfused slices or in the presence of paxilline; and (6) glybenclamide (20 µM), a K ATP channel blocker, decreased anoxia‐induced K + derangement, but DADLE (10 µM) could further attenuate anoxic K + derangement in the glybenclamide‐perfused slices. These data suggest that DOR, but not MOR, activation is protective against anoxic K + derangement in the cortex, at least partially via an inhibition of hypoxia‐induced increase in Ca 2+ entry‐BK channel activity. J. Cell. Physiol. 212: 60–67, 2007. © 2007 Wiley‐Liss, Inc.