Ionic storm in hypoxic/ischemic stress: can opioid receptors subside it?
Neurons in the mammalian central nervous system are extremely vulnerable to oxygen deprivation and blood supply insufficiency. Indeed, hypoxic/ischemic stress triggers multiple pathophysiological changes in the brain, forming the basis of hypoxic/ischemic encephalopathy. One of the initial and crucial events induced by hypoxia/ischemia is the disruption of ionic homeostasis characterized by enhanced K(+) efflux and Na(+)-, Ca(2+)- and Cl(-)-influx, which causes neuronal injury or even death. Recent data from our laboratory and those of others have shown that activation of opioid receptors, particularly delta-opioid receptors (DOR), is neuroprotective against hypoxic/ischemic insult. This protective mechanism may be one of the key factors that determine neuronal survival under hypoxic/ischemic condition. An important aspect of the DOR-mediated neuroprotection is its action against hypoxic/ischemic disruption of ionic homeostasis. Specially, DOR signal inhibits Na(+) influx through the membrane and reduces the increase in intracellular Ca(2+), thus decreasing the excessive leakage of intracellular K(+). Such protection is dependent on a PKC-dependent and PKA-independent signaling pathway. Furthermore, our novel exploration shows that DOR attenuates hypoxic/ischemic disruption of ionic homeostasis through the inhibitory regulation of Na(+) channels. In this review, we will first update current information regarding the process and features of hypoxic/ischemic disruption of ionic homeostasis and then discuss the opioid-mediated regulation of ionic homeostasis, especially in hypoxic/ischemic condition, and the underlying mechanisms.
Chao
Dongman
D
Yale University School of Medicine, Department of Pediatrics, New Haven, CT 06520, USA.
Xia
Ying
Y
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D019610:Cytoprotection / Q000502:physiology*; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000503:physiopathology; D007473:Ion Channels / Q000378:metabolism; D007477:Ions / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D011957:Receptors, Opioid / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology
D007473:Ion Channels; D007477:Ions; D011957:Receptors, Opioid