Kappa-opioid receptor selectivity for ischemic neuroprotection with BRL 52537 in rats.
Kappa-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 x kg(-1) x h(-1)) at reperfusion for 22 h, 3). saline 15 min before reperfusion followed by nor-BNI (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h, or 4) nor-BNI (1 mg/kg) 15 min before reperfusion followed by BRL 52537 (1 mgx kg(-1)x h(-1)) and nor-BNI (1 mg x kg(-1) x 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.


CONCLUSIONS
The neuroprotective effect of selective kappa-opioid agonists in transient focal ischemia is via a selective action at the kappa-opioid receptors.
Zhang
Zhizheng
Z
*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.
Chen
Tsung-Ying
TY
Kirsch
Jeffrey R
JR
Toung
Thomas J K
TJK
Traystman
Richard J
RJ
Koehler
Raymond C
RC
Hurn
Patricia D
PD
Bhardwaj
Anish
A
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002540:Cerebral Cortex / Q000473:pathology; D003391:Cranial Nerves / Q000503:physiopathology; D007839:Functional Laterality / Q000502:physiology; D005684:Gait / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D002546:Ischemic Attack, Transient / Q000473:pathology* / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D008297:Male; D020768:Middle Cerebral Artery / Q000502:physiology; D009129:Muscle Tonus / Q000502:physiology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010146:Pain / Q000503:physiopathology; D010880:Piperidines / Q000494:pharmacology*; D011699:Putamen / Q000473:pathology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000187:drug effects*; D015431:Weight Loss / Q000502:physiology
C454101:1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine; D018696:Neuroprotective Agents; D010880:Piperidines; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone