The Role of κ Opioid Receptor in Brain Ischemia

• Published in: Critical care medicine Vol. 44; no. 12; p. e1219
• Main Authors: Chen, Chunhua, Xi, Chunhua, Liang, Xuan, Ma, Jingyuan, Su, Diansan, Abel, Ted, Liu, Renyu
• Format: Journal Article
• Language: English
• Published: United States 01.12.2016
• Subjects: Animals; Apoptosis - drug effects; Blotting, Western; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Brain Ischemia - physiopathology; Disease Models, Animal; Diterpenes, Clerodane - pharmacology; Male; Mice; Mice, Inbred C57BL; Naltrexone - analogs & derivatives; Naltrexone - pharmacology; Receptors, Opioid, kappa - agonists; Receptors, Opioid, kappa - antagonists & inhibitors; Receptors, Opioid, kappa - physiology; Reperfusion Injury - prevention & control
• ISSN: 1530-0293
• DOI: 10.1097/CCM.0000000000001959

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. Animal model. Laboratory. The middle cerebral artery occlusion model was established by 120 minutes of ischemia followed by 24-hour reperfusion in male adult mice. 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. 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. 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.