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.