The Role of [kappa] Opioid Receptor in Brain Ischemia.

Objectives: Our previous studies indicated that highly selective [kappa] opioid receptor agonists could protect the brain, indicating an important role of [kappa] opioid receptor agonist in brain ischemia. In this study, we investigated the role and related mechanisms of [kappa] 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 [kappa] opioid receptor agonist, were administered intranasally 10 minutes after initiation of reperfusion. Norbinaltorphimine (2.5 mg/kg, IP) as a [kappa] opioid receptor antagonist was administered in one group before administration of salvinorin A (50[mu]g/kg) to investigate the specific role of [kappa] opioid receptor. Measurements and Main Results: Infarct volume, [kappa] 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-[alpha] levels to investigate the role of apoptosis and inflammation. [kappa] 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 [mu]g/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-[alpha] in the penumbral areas. All these changes were blocked or alleviated by norbinaltorphimine. Conclusions: [kappa] opioid receptors were up-regulated and played a critical role in brain ischemia and reperfusion. [kappa] opioid receptor activation could potentially protect the brain and improve neurologic outcome via blood-brain barrier protection, apoptosis reduction, and inflammation inhibition. Copyright (C) by 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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