δ-Opioid receptors protect from anoxic disruption of Na+ homeostasis via Na+ channel regulation

Abstract

Hypoxic/ischemic disruption of ionic homeostasis, especially Na + influx and K + leakage, is a critical trigger of neuronal injury/death in the brain. There is, however, no promising strategy against such pathophysiological changes to protect the brain from hypoxic/ischemic injury. Here we present an exciting finding that activation of delta-opioid receptor (DOR), which is highly expressed in the cortex, reduced anoxic Na + influx and K + leakage in the cortex by restricting Na + influx through voltage-gated Na + channels. Furthermore, we show for the first time with direct evidence that DOR expression/activation indeed plays an inhibitory role in Na + channel regulation by decreasing the amplitude of sodium currents and increasing activation threshold of Na + channels. These first data have far-reaching impacts on understanding the intrinsic mechanism of neuronal responses to stress and provide novel insights into better solutions of hypoxic/ischemic encephalopathy and other neurological disorders such as epilepsy and pain.

Neuroprotection Against Hypoxic/Ischemic Injury: δ-Opioid Receptors and BDNF-TrkB Pathway

“…However, they differ widely with respect to their efficacies, potency, side-effects, clearance, and passage through the blood-brain barrier; refer to our previous articles [41, 53]. To the best of our knowledge, UFP-512 (H-Dmt-Tic-NH-CH[CH2-COOH]-Bid) is the most potent and specific DOR agonist, and Naltrindole is a well-accepted DOR antagonist [41, 53-58]. …”

From Acupuncture to Interaction betweenδ-Opioid Receptors and Na+Channels: A Potential Pathway to Inhibit Epileptic Hyperexcitability

“…Opioid receptors are members of the G-protein-coupled receptor superfamily [76], and can functionally couple with ion channels, including Na + channels [16, 17, 77]. Our previous data implied an interaction between opioid receptors and Na + channels.…”

“…Activation of presynaptic DOR by enkephalin prevents the increase in neuronal Nav1.7 in the dorsal root ganglia, which relieves pain in diabetic neuropathy [17]. More recently, our studies indicated that DOR activation attenuates hypoxic K + -Na + homeostasis, which largely relies on DOR inhibition of Na + influx through Na + channels [16, 18–22]. These results suggest that under pathological conditions DOR could mediate an inhibitory regulation of Na + channels in the brain.…”

“…We have previously demonstrated that electroacupuncture has a neuroprotective role in the brain against ischemic injury via the δ -opioid system [14, 15]. DOR expression/activation inhibits Na + channel activity [16, 17] and thus attenuates Na + -K + homeostasis of the cortex under normoxic/hypoxic conditions [16, 18–22]. Since the electrolyte homeostasis (e.g., Na + Ca 2+ , K + , and Cl − ) gets disrupted between the intra- and extracellular space during epileptic seizures, and since Na + channel upregulation participates in the pathological changes of several neurological disorders such as hypoxic/ischemic injury and epilepsy [23–26], acupuncture may attenuate epileptic seizures through the DOR-mediated inhibition of the Na + channels [1].…”

Expression of Voltage-Gated Sodium Channel Nav1.3 Is Associated with Severity of Traumatic Brain Injury in Adult Rats

“…10 VGSCs a subunits play an important role in different tissues. For example, Kang and coworkers 11 reported that VGSCs in the cortex were a major route for Na + influx during hypoxia and ischemia. Peripheral nerve injury caused by trauma or surgery may upregulate Nav1.3 and downregulate Nav1.8 in injured dorsal root ganglia, and intrathecal lidocaine pretreatment alleviates neuropathic pain by modulating Nav1.3 expression and decreasing spinal microglial activation.…”