The acid sensing ion channel1a (ASIC1a) is essential for normal brain function, but initiates neuronal death and contributes to ischemic brain injury. Prolonged reductions in extracellular pH accompany ischemia and ASIC1a inhibition limits neurological damage. Yet, ASICs also play an important role in normal physiology and established models of ASIC-induced cell death make it difficult to develop strategies that specifically inhibit ASIC1a toxicity. Our preliminary data support a newer model of ASIC1a-induced cell death. Specifically, we have discovered that the toxic effect of ASIC1a can be eliminated by modification of the intracellular region of the channel or activation of the delta opioid receptor (DOR). An especially provocative aspect of these findings is that acidotoxicity is inhibited without a reduction in ASIC1a current, thereby suggesting that the toxic and physiological actions of the channel can be separated. Our central hypothesis is that DOR prevents acidotoxicity through signaling cascades, which act on the intracellular domain of ASIC1a to limit protein interactions required for toxicity. To test this hypothesis, we will define the mechanisms governing DOR action on ASIC1a and elucidate their role in ischemic injury in vivo. The outcomes of the proposed work will reveal novel regulatory mechanisms controlling ASIC1a-induced toxicity, suggest new interventions to mitigate ASIC-induced death using existing DOR agonists, and reveal strategies to separate the physiological and pathological actions of ASIC1a. These results will be significant as they are expected to have broad implications for the prevention of brain injury following ischemic stroke as well as other disorders where neuronal acidotoxicity plays a role.