δ Opioid Receptor/DOR

The δ-opioid receptor (DOR) is a G protein-coupled receptor (GPCR) that modulates neuronal signaling, particularly within pain and stress response pathways^[1][2]. Mechanistically, DOR activation influences intracellular cascades including phospholipase A2 (PLA2), cAMP/protein kinase A (PKA), protein kinase C (PKC), extracellular signal-regulated kinases (ERKs), and p38 mitogen-activated protein kinase (MAPK), contributing to synaptic transmission modulation and cellular stress responses^{[1][3][4][5][6][7][8]}. In disease models, DOR exerts neuroprotective effects during hypoxic/ischemic injury, reduces tau hyperphosphorylation, regulates β-site APP cleaving enzyme 1 (BACE1) in Alzheimer’s pathology, and mitigates microglial overactivation, demonstrating its relevance in neurodegeneration and neuroinflammation^[2][3][6][9]. Compared with µ-opioid receptors (MORs), DOR exhibits distinct functional profiles, including neuroprotective signaling and opposing modulation of amyloidogenic pathways, as well as differential receptor heteromerization dynamics with MOR in both central and peripheral nervous systems^[1][2][5][6]. Selective DOR agonists such as UFP-512, KNT-127, and DPDPE facilitate analgesia, neuroprotection, and fear extinction through activation of specific brain regions and downstream pathways, while DOR antagonists like naltrindole reverse these effects, providing a practical framework for experimental applications^{[3][4][10][11]}. These findings position DOR as a distinct molecular target with broad utility in neurodegenerative, cardiac, and pain-related research contexts^[7][12][13].