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Acid-sensing ion channel 1a (ASIC1a) promotes neuronal death in pathological acidosis, however, little is known regarding ASIC1a-dependent acidotoxicity and whether it can be regulated by signaling pathways. We have discovered connections between ASICs and the endogenous opioid system. Prior research has shown activation of the delta-opioid receptor (DOR) to be neuroprotective in mouse models of ischemic injury. Recently, we determined that DOR activation also attenuates ASIC1a-induced neuronal death. We hypothesized that DOR agonists limit ASIC1a toxicity through a unique mechanism. To this end, we found that enkephalins (endogenous agonists of DOR) limit ASIC1-dependent acidotoxicity in primary neuron cultures. This neuroprotection was sensitive to DOR-specific antagonists and protein kinase-C inhibition. Interestingly, ASIC currents appear unaffected by DOR activation, suggesting that DOR attenuates ASIC1a-induced toxicity through a novel mechanism that does not involve inhibition of channel activity. ASIC and DOR expression overlap in the central nervous system and met-enkephalin has been shown to colocalize with ASIC, however this is the first report of DOR affecting ASIC-dependent processes. Further, the fact that ASIC1a current is unchanged suggests that DOR activation specifically targets ASIC1a pathological activity and spares ASIC’s physiological role in neurotransmission. Ultimately, we hope this observation could yield insight into therapeutics for ischemic stroke, a leading cause of death lacking effective clinical treatments.