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The Role of κ Opioid Receptor in Brain Ischemia
Chunhua Chen1, Chunhua Xi, Xuan Liang
11Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.2Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.3Department of Anesthesiology, Renji Hospital, Jiaotong University School of Medicine, Shanghai, China.4Department of Biology, University of Pennsylvania, Philadelphia, PA.
Objectives:
Our previous studies indicated that highly selective κ opioid receptor agonists could protect the brain, indicating an important role of κ opioid receptor agonist in brain ischemia. In this study, we investigated the role and related mechanisms of κ opioid receptor agonists in brain ischemia in a middle cerebral artery occlusion mouse model.
Design:
Animal model.
Setting:
Laboratory.
Subjects:
The middle cerebral artery occlusion model was established by 120 minutes of ischemia followed by 24-hour reperfusion in male adult mice.
Interventions:
Various doses of salvinorin A, a highly selective and potent κ opioid receptor agonist, were administered intranasally 10 minutes after initiation of reperfusion. Norbinaltorphimine (2.5 mg/kg, IP) as a κ opioid receptor antagonist was administered in one group before administration of salvinorin A (50μg/kg) to investigate the specific role of κ opioid receptor.
Measurements And Main Results:
Infarct volume, κ opioid receptor expression, and Evans blue extravasation in the brain, and neurobehavioral outcome were determined. Immunohistochemistry and western blot were performed to detect the activated caspase-3, interleukin-10, and tumor necrosis factor-α levels to investigate the role of apoptosis and inflammation. κ opioid receptor expression was elevated significantly in the ischemic penumbral area compared with that in the nonischemic area. Salvinorin A reduced infarct volume and improved neurologic deficits dose-dependently. Salvinorin A at the dose of 50 μg/kg reduced Evans blue extravasation, suggesting reduced impairment of the blood-brain barrier and decreased the expression of cleaved caspase-3, interleukin-10, and tumor necrosis factor-α in the penumbral areas. All these changes were blocked or alleviated by norbinaltorphimine.
Conclusions:
κ opioid receptors were up-regulated and played a critical role in brain ischemia and reperfusion. κ opioid receptor activation could potentially protect the brain and improve neurologic outcome via blood-brain barrier protection, apoptosis reduction, and inflammation inhibition.
Insights
Highly selective kappa opioid receptor agonists, like salvinorin A, show neuroprotective effects in mouse models of brain ischemia. Activation of these receptors reduces infarct volume, improves neurological deficits, and inhibits apoptosis and inflammation.
Area of Science:
- Neuroscience
- Pharmacology
- Ischemic Stroke Research
Background:
- Previous studies suggest kappa opioid receptor agonists possess neuroprotective properties.
- Brain ischemia involves complex pathological processes including apoptosis and inflammation.
Purpose of the Study:
- To investigate the role and mechanisms of kappa opioid receptor agonists in a mouse model of middle cerebral artery occlusion (MCAO).
- To evaluate the neuroprotective effects of salvinorin A, a selective kappa opioid receptor agonist, in MCAO mice.
Main Methods:
- Establishment of a middle cerebral artery occlusion (MCAO) model in adult male mice with 120 minutes of ischemia and 24-hour reperfusion.
- Intranasal administration of varying doses of salvinorin A post-reperfusion; administration of norbinaltorphimine (kappa opioid receptor antagonist) to assess specificity.
- Assessment of infarct volume, kappa opioid receptor expression, blood-brain barrier integrity (Evans blue extravasation), neurobehavioral outcomes, and levels of apoptosis (caspase-3) and inflammation (IL-10, TNF-α).
Main Results:
- Kappa opioid receptor expression was significantly upregulated in the ischemic penumbra.
- Salvinorin A demonstrated a dose-dependent reduction in infarct volume and improvement in neurological deficits.
- Salvinorin A (50 μg/kg) reduced blood-brain barrier permeability, decreased cleaved caspase-3, IL-10, and TNF-α levels.
- The effects of salvinorin A were significantly attenuated by the kappa opioid receptor antagonist, norbinaltorphimine.
Conclusions:
- Kappa opioid receptors are upregulated and play a critical role in brain ischemia-reperfusion injury.
- Activation of kappa opioid receptors offers potential neuroprotection by preserving the blood-brain barrier, reducing apoptosis, and inhibiting inflammation.
- Salvinorin A represents a promising therapeutic agent for mitigating brain ischemia-reperfusion damage.
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