Neuroprotection against hypoxia/ischemia: δ-opioid receptor-mediated cellular/molecular events

Abstract

Hypoxic/ischemic injury remains the most dreaded cause of neurological disability and mortality. Despite the humbling experiences due to lack of promising therapy, our understanding of the complex cascades underlying the neuronal insult has led to advances in basic science research. One of the most noteworthy has been the effect of opioid receptors, especially the delta-opioid receptor (DOR), on hypoxic/ischemic neurons. Our recent studies, and those of others worldwide, present strong evidence that sheds light on DOR-mediated neuroprotection in the brain, especially in the cortex. The mechanisms of DOR neuroprotection are broadly categorized as: (1) stabilization of the ionic homeostasis, (2) inhibition of excitatory transmitter release, (3) attenuation of disrupted neuronal transmission, (4) increase in antioxidant capacity, (5) regulation of intracellular pathways-inhibition of apoptotic signals and activation of pro-survival signaling, (6) regulation of specific gene and protein expression, and (7) up-regulation of endogenous opioid release and/or DOR expression. Depending upon the severity and duration of hypoxic/ischemic insult, the release of endogenous opioids and DOR expression are regulated in response to the stress, and DOR signaling acts at multiple levels to confer neuronal tolerance to harmful insult. The phenomenon of DOR neuroprotection offers a potential clue for a promising target that may have significant clinical implications in our quest for neurotherapeutics.

Fig. 1

Overview of the mechanisms underlying DOR neuroprotection

Fig. 2

DOR effect on ionic homeostasis in hypoxic/ischemic stress. BK Ch Calcium-activated potassium channels. DOR delta-opioid receptor, TRK tyrosine kinase, Na ⁺ Ch sodium channels, Ca ²⁺ Ch calcium channels, NMDA Ch NMDA channels, K ⁺ Ch potassium channels. Arrows in red indicate the effect of hypoxic/ischemic effects, dashed lines indicate inhibition, and green arrows/lines indicate the survival or neuroprotective mechanisms or changes

Fig. 3

DOR-mediated cellular and molecular regulation in prolonged hypoxia/ischemia. ROS reactive oxygen species or oxygen free radicals, HPC hypoxic pre-conditioning, HIF hypoxia inducible factor, EO endogenous opioids, SOD superoxide dismutase, MPTP mitochondrial permeability transition pore. Arrows in red indicate effect of hypoxic/ischemic effects; dashed lines indicate inhibition; and green arrows/lines indicate the survival or neuroprotective mechanisms or changes. Blue ovals represent components involved in the neuroprotective pathways while red hexagons represent components playing role in the hypoxic/ischemic cell injury