The Role of κ Opioid Receptor in Brain Ischemia

Abstract

Objectives Our previous studies indicated that highly selective kappa opioid receptor (KOR) agonists could protect the brain, indicating an important role of KOR agonist in brain ischemia. In this study, we investigated the role and related mechanisms of KOR agonists in brain ischemia in a middle cerebral artery occlusion (MCAO) mouse model. Subjects and Interventions The MCAO model was established by 120 minutes of ischemia followed by 24 h reperfusion in male adult mice. Various doses of salvinorin A (SA), a highly selective and potent KOR agonist, were administered intranasally 10 min after initiation of reperfusion. Norbinaltorphimine (2.5 mg/kg, i.p.) as a KOR antagonist was administered in one group before administration of SA (50 µg/kg) to investigate the specific role of KOR. After 24 h reperfusion, neurobehavioral outcome was determined. Infarct volume, KOR expression, and Evans blue extravasation in the brain were determined. Immunohistochemistry and western blot were performed to detect the activated caspase-3, IL-10 and TNF-alpha levels to investigate the role of apoptosis and inflammation. Main Results KOR expression was elevated significantly in the ischemic penumbral area compared to that in the non-ischemic area. SA reduced infarct volume and improved neurological deficits dose-dependently. SA 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 casepase-3, IL-10 and TNF-alpha in the penumbral areas. All these changes were blocked or alleviated by norbinaltorphimine. Conclusions KORs were up-regulated and played a critical role in brain ischemia and reperfusion. KOR activation could potentially protect the brain and improve neurological outcome via blood brain barrier protection, apoptosis reduction and inflammation inhibition.

Antioxidant Properties and Protective Effects of Some Species of the Annonaceae, Lamiaceae, and Geraniaceae Families against Neuronal Damage Induced by Excitotoxicity and Cerebral Ischemia

“…The main active constituent isolated from the leaves of S. divinorum is the neoclerodane diterpene salvinorin A, which has shown reduced infarct volume and improved neurological deficits. It also reduced Evans blue extravasation, suggesting reduced impairment of the blood-brain barrier, and decreased the expression of cleaved casepase-3, IL-10, and TNF-alpha in the penumbral areas, preventing apoptosis and reducing inflammation [27]. Thus, our results suggest that extracts from Lamiaceae could be an alternative for treating cerebral ischemia, but it will be necessary to characterize the components of the extract; that is, the identification and evaluation of the active compounds will be required to elucidate its mechanism of action in the induced protection against cerebral ischemia…”

“…The bioactive clerodane diterpenes are abundant in both species [26]. Clerodanes can be used to activate opioid receptors and protect against cerebral ischemia [27].…”

Hypoxia Induces Internalization of κ-Opioid Receptor

“…The indirect evidence for such statement is that SA, the highly selectively KOR agonist, can induce KOR internalization similar to that by hypoxia and SA could protect the brain from hypoxia and ischemia, resulting improved neurological outcome as we have demonstrated in a rodent model of brain ischemia. 48 Further experiments are needed to investigate whether naïve KORs in primary neuronal cultures undergo similar trafficking as in neuroblastoma cells with KOR over-expression.…”

Salvinorin A ameliorates cerebral vasospasm through activation of endothelial nitric oxide synthase in a rat model of subarachnoid hemorrhage

“…The regulation of AQP‐4 was associated with brain edema, and its expression in brain peaks at 24‐72 hour post–brain injury, which coincides with brain edema development . Salvinorin A (SA) is a selective kappa opioid receptor (KOR) agonist, which could dilate the pial artery with high potency and maintain the cerebral autoregulation . Highly lipophilic structure of SA allows it to diffuse through the blood‐brain barrier easily .…”

“…14 Salvinorin A (SA) is a selective kappa opioid receptor (KOR) agonist, which could dilate the pial artery with high potency and maintain the cerebral autoregulation. 15,16 Highly lipophilic structure of SA allows it to diffuse through the blood-brain barrier easily. 17,18 We have demonstrated that SA can preserve cerebrovascular autoregulatory ability after hypoxia/ischemia 19 and dilate pial arteries via activation of nitric oxide synthase (NOS).…”