Current Research on the δ-Opioid Receptor: From Neuroprotection Against Hypoxia/Ischemia to Broad Neural Functions

Abstract

The delta-opioid receptor (DOR) was traditionally thought to be primarily involved in modulating the transmission of messages along pain pathways. Therefore, most previous studies focused on its function in pain modulation. Although there were scattered studies on other functions, inconsistent results and contradicting conclusions were present in the past literature, especially in terms of DOR and neuroprotection against hypoxic/ischemic injury. Based on our observations on the evolutionary developmental distribution of DOR in the brain, and taking inspiration from the finding that the turtle brain exhibited a much higher DOR density and greater tolerance to hypoxic/ischemic insult, we clarified DOR’s specific role in the brain against hypoxic/ischemic injury and reconciled previous controversies in this aspect. Furthermore, we expanded our work to other neural functions and achieved significant progress. Our first finding showed that DOR is an endogenous inhibitor of sodium channels, and DOR signaling is involved in the maintenance of ionic homeostasis stabilization in physiological conditions as well as under hypoxic/ischemic stress. DOR activation upregulates the expression of astrocytic glutamate transporters and increases astrocytic ability to clean up extracellular glutamate accumulation. DOR signals promote the function of Nrf2 in both neurons and glia. DOR can also exert a beneficial action against Parkinson’s disease and its activation reduces α-synuclein overexpression and oligomer formation in in vitro models of Parkinson’s disease. DOR activation prevents the collapse of mitochondrial membrane potential, thereby reducing cell injury. In addition to DOR neuroprotection against ischemic injury in the model of ischemic stroke, DOR acts as a major mediator in electroacupuncture-induced brain protection against cerebral ischemia. The DOR system may also serve as an inhibitor of epileptic hyperexcitability through the inhibition of sodium channel function, which would explain the positive effects electroacupuncture has on epilepsy. Apart from our research, recent studies from other independent laboratories consistently show a variety of functions for DOR that are mostly beneficial, including neurogenesis, in the brain and heart. On the other hand, dysfunction of DOR may be involved in the pathophysiological events of many diseases. An in-depth understanding of DOR’s functions and the underlying mechanisms and development of more effective DOR ligands will eventually open a door for the prevention and treatment of many neurological and other diseases in the future.