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

Abstract

The delta-opioid receptor (DOR) is one of three classic opioid receptors in the opioid system. It was traditionally thought to be primarily involved in modulating the transmission of messages along pain signaling pathway. Although there were scattered studies on its other neural functions, inconsistent results and contradicting conclusions were found in past literatures, especially in terms of DOR’s role in a hypoxic/ischemic brain. Taking inspiration from the finding that the turtle brain exhibits a higher DOR density and greater tolerance to hypoxic/ischemic insult than the mammalian brain, we clarified DOR’s specific role in the brain against hypoxic/ischemic injury and reconciled previous controversies in this aspect. Our serial studies have strongly demonstrated that DOR is a unique neuroprotector against hypoxic/ischemic injury in the brain, which has been well confirmed in current research. Moreover, mechanistic studies have shown that during acute phases of hypoxic/ischemic stress, DOR protects the neurons mainly by the stabilization of ionic homeostasis, inhibition of excitatory transmitter release, and attenuation of disrupted neuronal transmission. During prolonged hypoxia/ischemia, however, DOR neuroprotection involves a variety of signaling pathways. More recently, our data suggest that DOR may display its neuroprotective role via the BDNF-TrkB pathway. This review concisely summarizes the progress in this field.

δ-Opioid receptor activation ameliorates lipopolysaccharide-induced inflammation and apoptosis by inhibiting the MAPK/caspase-3 pathway in BV2 microglial cells

“…Delta-opioid receptor (DOR) is a member of the opioid receptor superfamily and is widely expressed throughout the CNS (Chao and Xia 2015). Endogenous and exogenous DOR activation regulates a variety of signalling pathways, including the protein kinase A (PKA), mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and brainderived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) pathways to exert diverse effects, such as antinociceptive, antidepressant, and neuroprotective effects (Chu Sin Chung and Kieffer 2013;Sheng et al 2018). More importantly, a growing body of evidence has shown that the neuroprotective effect of DOR activation is related to MAPK signalling during ischaemia/hypoxia.…”

Ginkgo biloba L. Prevents Hypobaric Hypoxia–Induced Spatial Memory Deficit Through Small Conductance Calcium-Activated Potassium Channel Inhibition: The Role of ERK/CaMKII/CREB Signaling

“…We further explored the putative signaling pathway involved in GBE-mediated neuroprotection. BDNF is well known to promote cell survival and neuroprotection in control conditions as well as in different pathological conditions ( Sheng et al, 2018 ). A study by Kramár et al showed that BDNF decreases the SK2 component by phosphorylation, causes its inactivation, and strengthens synaptic transmission ( Kramar et al, 2004 ).…”

β-Funaltrexamine Displayed Anti-Inflammatory and Neuroprotective Effects in Cells and Rat Model of Stroke

“…Clinically, cancer patients undergoing intensive morphine treatment have an increased risk of stroke incidence [34]. Accordingly, a growing body of evidence has revealed the neuroprotective effects of the nonselective opioid receptor antagonist naloxone, δ opioid receptor agonists, and κ opioid receptor agonists in rodent models experiencing neurodegeneration [3,7,[9][10][11][24][25][26][35][36][37]. Being a CNS-penetrating compound, the selective µ opioid receptor antagonist β-funaltrexamine is capable of inhibiting LPS-induced neuroinflammation in mice after receiving an intraperitoneal injection [29,30].…”

“…Beyond its effect on the nociceptive/analgesic systems, the opioidergic system also displays effects on physiological and behavioral functions, including respiration, ion channel activity, and immune responses [1,2]. Additionally, alteration in the opioidergic system has been reported in the disease initiation and progression of several acute and chronic diseases, including neurodegenerative diseases [3][4][5][6][7][8][9]. These phenomena highlight the potential pathogenic roles that the opioidergic system may have and candidate targets for intervention with an aim to prevent and/or treat diseases.…”

“…Upon binding with either the µ, δ, or κ opioid receptor, they display shared or distinct biological consequences. For example, the neuroprotective effects of the δ and κ opioid receptor agonists and µ opioid receptor antagonist have been described [7,[9][10][11]. Despite morphine long being known to have immunosuppressive properties in vivo, a chronic morphine infusion causes neuroinflammation [12,13].…”