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.
IMPLICATIONS: