Prolonged Opportunity for Ischemic Neuroprotection with Selective -Opioid Receptor Agonist in Rats
From the Departments of Anesthesiology/Critical Care Medicine (T.-Y. C., T.G., T.J.K.T., J.R.K., P.D.H., R.C.K., A.B.) and Neurology (A.B.), Johns Hopkins University School of Medicine, Baltimore, Md; Department of Anesthesiology and Peri-operative Medicine (J.R.K., P.D.H.), Oregon Health and Science University, Portland, Ore.
Background and Purpose— We have previously demonstrated that pretreatment with selective -opioid agonist BRL 52537 hydrochloride [(±)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine], provides ischemic neuroprotection following transient focal ischemia in rats. The present study was undertaken to a) define "therapeutic opportunity" for ischemic neuroprotection with BRL 52537, and b) determine if BRL 52537 attenuates ischemia-evoked efflux of dopamine and its metabolites in the striatum in vivo following transient focal ischemia.
Methods— Using the intraluminal filament technique, halothane-anesthetized male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAO). In a blinded, randomized fashion, rats were treated with saline (vehicle) or 1 mg/Kg/hr BRL 52537 infusion for 22 hours, initiated at onset, 2, 4, or 6 hours of reperfusion (Rep). In a separate set of experiments utilizing in vivo microdialysis, extracellular levels of dopamine and its metabolites were determined in the striatum during 2 hours of MCAO and 3 hours of reperfusion.
Results— Infarct volume (% of contralateral structure; mean ±SEM) in cortex was significantly attenuated when BRL 52537 was administered at reperfusion (22±6%), 2 hours (21±6%), and 4 hours (18±5%) compared with controls (39±5%). In striatum, infarct volume was significantly attenuated when BRL 52537 was administered at reperfusion (38±9%), 2 hours (40±8%), 4 hours (50±8%), and 6 hours (46±9%) as compared with controls (70±4%). A 6- to 8-fold increase in dopamine in microdialysates occurred within 40 minutes of MCAO. Pretreatment with BRL 52537 did not alter microdialysate levels of dopamine or its metabolites in the striatum during MCAO and early reperfusion, as compared with saline controls.
Conclusions— These data demonstrate that BRL 52537 provides robust ischemic neurprotection with a long therapeutic opportunity (at least 6 hours) without altering ischemia-evoked efflux of dopamine (DA) and its metabolites in striatum during ischemia and early reperfusion.
Morphine Preconditions Purkinje Cells against Cell Death under In Vitro Simulated Ischemia-Reperfusion Conditions.
Anesthesiology. 100(3):562-568, March 2004.
Lim, Young Jin M.D., Ph.D. *; Zheng, Shuqiu M.D., Ph.D. +; Zuo, Zhiyi M.D., Ph.D. ++
Abstract:
Background: Morphine pretreatment via activation of [delta]1-opioid receptors induces cardioprotection. In this study, the authors determined whether morphine preconditioning induces ischemic tolerance in neurons.
Methods: Cerebellar brain slices from adult Sprague-Dawley rats were incubated with morphine at 0.1-10 [mu]m in the presence or absence of various antagonists for 30 min. They were then kept in morphine- and antagonist-free buffer for 30 min before they were subjected to simulated ischemia (oxygen-glucose deprivation) for 20 min. After being recovered in oxygenated artificial cerebrospinal fluid for 5 h, they were fixed for morphologic examination to determine the percentage of undamaged Purkinje cells.
Results: The survival rate of Purkinje cells was significantly higher in slices preconditioned with morphine (>= 0.3 [mu]m) before the oxygen-glucose deprivation (57 +/- 4% at 0.3 [mu]m morphine) than that of the oxygen-glucose deprivation alone (39 +/- 3%, P < 0.05). This morphine preconditioning-induced neuroprotection was abolished by naloxone, a non-type-selective opioid receptor antagonist, by naltrindole, a selective [delta]-opioid receptor antagonist, or by 7-benzylidenenaltrexone, a selective [delta]1-opioid receptor antagonist. However, the effects were not blocked by the [mu]-, [kappa]-, or [delta]2-opioid receptor antagonists, [beta]-funaltrexamine, nor-binaltorphimine, or naltriben, respectively. Morphine preconditioning-induced neuroprotection was partially blocked by the selective mitochondrial adenosine triphosphate-sensitive potassium channel antagonist, 5-hydroxydecanoate, or the mitochondrial electron transport inhibitor, myxothiazol. None of the inhibitors used in this study alone affected the simulated ischemia-induced neuronal death.
Conclusions: These data suggest that morphine preconditioning is neuroprotective. This neuroprotection may be [delta]1-opioid receptor dependent and may involve mitochondrial adenosine triphosphate-sensitive potassium channel activation and free radical production. Because morphine is a commonly used analgesic, morphine preconditioning may be explored further for potential clinical use to reduce ischemic brain injury.
Opioids are commonly used analgesics in clinical practice. Three opioid receptors (m, d and k) that mediate opioid effects have been identified by molecular cloning. Each type of opioid receptors consists of subtypes of receptors as suggested by pharmacological studies. Although m opioid receptors are the major receptor to mediate the analgesic effects of opioids, d and k receptors are also important in anti-nociception (for example, d and k receptors can mediate spinal analgesia).
Recently, the cytoprotective effects of opioids have been recognized. The presence of opioids during harmful events such as ischemia reduces cell injury in multiple organs including heart and brain. These effects appear to be mediated by d receptors in most studies. A new form of cytoprotection in which a prior exposure to opioids renders protection against cell ischemia (opioid preconditioning) has been identified. In the heart, this opioid preconditioning-induced protection has been well documented by multiple studies and may be mediated by d receptors, Gi/o proteins, protein kinase C, ATPsensitive potassium channels and free radicals. Our initial study suggests that opioid preconditioning also induces neuroprotection. This neuroprotection involves d1 receptors, mitochondrial ATP-sensitive potassium channels and free radical production.
U. Barry and Z. Zuo
Some additional sources:
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2) Goyagi T, Bhardwaj A, Koehler RC, Traystman RJ, Hurn PD, Kirsch JR. Potent sigma 1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine provides ischemic neuroprotection without altering dopamine accumulation in vivo in rats. Anesth Analg. 2003; 96: 532–538
3) Zhang Z, Chen T-Y, Kirsch JR, Toung TJK, Traystman RJ, Koehler RC, Hurn PD. Kappa-opioid receptor selectivity for ischemic neuroprotection with BRL 52537 in rats. Anesth Analg. 2003; 97: 1776–1783
