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NEUROSURGICAL ANESTHESIA

Kappa-Opioid Receptor Selectivity for Ischemic Neuroprotection with BRL 52537 in Rats

Zhizheng Zhang, MD^*, Tsung-Ying Chen, MD, Jeffrey R. Kirsch, MD^*, Thomas J. K. Toung, MD, Richard J. Traystman, PhD^*, Raymond C. Koehler, PhD, Patricia D. Hurn, PhD^*, and Anish Bhardwaj, MD^,

*Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon; and Departments of Anesthesiology/Critical Care Medicine and Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Address correspondence and reprint requests to Anish Bhardwaj, MD, Neuroscience Critical Care Division, Meyer 8-140, Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21287. Address e-mail to abhardwa{at}jhmi.edu

-Opioid receptors (KOR) have been implicated in neuroprotection from ischemic neuronal injury, but less work has been performed with transient focal cerebral ischemia to determine the role of KOR during reperfusion. We tested the effects of a selective and specific KOR agonist, BRL 52537 hydrochloride [(±)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine], and the standard KOR antagonist, nor-binaltorphimine dihydrochloride [nor-BNI; 17,17'-(dicyclopropylmethyl)-6,6',7,7'-6,6'-imino-7,7'-binorphinan-3,4',14,14'-tetrol], on functional and histological outcome after transient focal ischemia in the rat. By use of the intraluminal filament technique, halothane-anesthetized adult male Wistar rats were subjected to 2 h of middle cerebral artery occlusion confirmed by laser Doppler flowmetry. In a blinded, randomized fashion, rats were treated with 1) saline (vehicle) 15 min before reperfusion followed by saline at reperfusion for 22 h, 2) saline 15 min before reperfusion followed by BRL 52537 (1 mg · kg^-1 · h^-1) at reperfusion for 22 h, 3) saline 15 min before reperfusion followed by nor-BNI (1 mg · kg^-1 · h^-1) at reperfusion for 22 h, or 4) nor-BNI (1 mg/kg) 15 min before reperfusion followed by BRL 52537 (1 mg · kg^-1 · h^-1) and nor-BNI (1 mg · kg^-1 · h^-1) at reperfusion for 22 h. Infarct volume (percentage of ipsilateral structure) analyzed at 4 days of reperfusion was significantly attenuated in saline/BRL 52537 rats (n = 8; cortex, 10.2% ± 4.3%; caudoputamen [CP], 23.8% ± 6.7%) (mean ± SEM) compared with saline/saline treatment (n = 8; cortex, 28.6% ± 4.9%; CP, 53.3% ± 5.8%). Addition of the specific KOR antagonist nor-BNI to BRL 52537 completely prevented the neuroprotection (n = 7; cortex, 28.6% ± 5.3%; CP, 40.9% ± 6.2%) conferred by BRL 52537. BRL 52537 did not produce postischemic hypothermia. These data demonstrate that KORs may provide a therapeutic target during early reperfusion after ischemic stroke.

IMPLICATIONS: The neuroprotective effect of selective -opioid agonists in transient focal ischemia is via a selective action at the kappa-opioid receptors.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999