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Both in vivo and in vitro studies have shown the beneficial effects of the delta-opioid receptor (DOR) on neurodegeneration in hypoxia/ischemia.We previously reported that DOR stimulation with [(D-Ala2,D-Leu5) enkephalin] (DADLE),a potent DOR agonist,for both a short (minutes) and long (days) time has notable protective effects against sodium azide (NaN3)-induced cell injury in primary cultured rat cortical neurons.We further demonstrated that short-term DADLE stimulation increased neuronal survival through the PKC-mitochondrial ERK pathway.However,the mechanisms underlying long-term neuroprotection by DADLE remain unclear.Here,we showed that DOR stimulation with DADLE (0.1 μmol/L) for 2 d selectively activates the PI3K/Akt/NF-κB pathway in NaN3-treated neurons;this activation increased Bcl-2 expression,attenuated Cyto c release and promoted neuronal survival.Further investigation revealed that sustained DADLE stimulation increased Bcl-2 expression by enhancing NF-κB binding to the Bcl-2 promoter and upregulating the histone acetylation levels of the Bcl-2 promoter.Our results demonstrate that prolonged DADLE exposure epigenetically promotes Bcl-2 expression and elicits neuroprotective effects in the NaN3 model via the PI3K/Akt/NF-κB pathway.