norbinaltorphimine and Ischemic-Attack--Transient

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

Topics: Animals; Behavior, Animal; Cerebral Cortex; Cranial Nerves; Functional Laterality; Gait; Hemodynamics; Ischemic Attack, Transient; Laser-Doppler Flowmetry; Male; Middle Cerebral Artery; Muscle Tonus; Naltrexone; Neuroprotective Agents; Pain; Piperidines; Putamen; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid, kappa; Weight Loss

Transient ischemia produced marked memory dysfunctions in mice on three different tasks, spontaneous alternation, elevated plus-maze and passive avoidance, as tested 1, 1-2, and 2-3 days after ischemic insult, respectively. U-50,488H, a kappa-opioid receptor agonist, administered 20 min before ischemic insult markedly prevented the impairment of spontaneous alternation, the prolongation of transfer latency in elevated-plus maze and the shortening of step-through latency in passive avoidance induced by transient ischemia. The protective effect of U-50,488H (30 mg/kg) on ischemia-induced memory dysfunctions observed in the three tasks was almost completely reversed by pretreatment with nor-binaltorphimine (4 micrograms, i.c.v.), a kappa-selective opioid antagonist. Although U-50,488H (30 mg/kg) did not affect body temperature in sham mice, it blocked hypothermia induced by ischemic insult. These results suggest that the protective effect of U-50,488H on memory dysfunctions in ischemic mice is associated with the activation of kappa-opioid receptors and is not based upon hypothermia.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Amnesia; Analgesics; Animals; Avoidance Learning; Body Temperature; Drug Interactions; Ischemic Attack, Transient; Learning; Male; Memory; Mice; Mice, Inbred Strains; Naltrexone; Pyrrolidines; Receptors, Opioid, kappa; Reperfusion; Time Factors