Role of delta‐opioid and adenosine receptors in preventing NMDA receptor dependent excitotoxicity in anoxic turlte cortex

Abstract

Delta‐opioid (DOR) and adenosine A1 (A1R) receptor activation are neuroprotective against short‐term anoxic insults in mammalian brain. Protection may be conferred by inhibition of N‐methyl‐D‐aspartate receptors (NMDARs); activation of which leads to excitotoxic cell death (ECD). In anoxic turtle cortex NMDAR activity decreases 50% and ECD is avoided. DORs and A1Rs are expressed in turtle brain but their roles in anoxic turtle brain NMDAR regulation have not been investigated. DOR blockade with naltrindole potentiated normoxic NMDAR currents by 78%, and increased [Ca2+]c 13%. Anoxic neurons treated with naltrindole were strongly depolarized, NMDAR currents were potentiated 70%, and [Ca2+]c increased 5‐fold above anoxic controls. The naltrindole‐mediated depolarization and increased [Ca2+]c were prevented by NMDAR antagonism or by perfusion of the Gi protein agonist mastoparan, which also reversed the naltrindole‐mediated potentiation. Normoxic agonism of A1Rs with CPA decreased NMDAR currents by 58% but antagonism during anoxia with DPCPX did not prevent the anoxia‐mediated decrease. The Gi protein inhibitor pertusis toxin (PTX) prevented both the CPA and anoxia‐mediated decreases in NMDAR currents. Our results suggest that the long‐term anoxic decrease in NMDAR activity is activated by a PTX‐sensitive mechanism that maybe be related by DORs but is independent of A1Rs.