NEUROPROTECTIVE EFFECTS OF KAPPA OPIOID RECEPTOR AGONIST IN TRANSIENT FOCAL ISCHEMIA
Kappa (K) opioid receptors have been implicated in neuroprotection from ischemic neuronal injury. We tested the effects of a selective and specific K-opioid receptor agonist, BRL 52537 and antagonist, norBNI on infarction volume following transient focal ischemia in the rat. Under controlled conditions of normoxia, normocarbia and normothermia, halothane (1–2%)-anesthetized male Wistar rats (250–300 g) were subjected to 2 hr of middle cerebral artery occlusion (MCAO) by the intraluminal occlusion-technique using laser Doppler perfusion to assess intensity of ischemia. In a blinded randomized fashion, rats were treated with either vehicle (saline) or 1 mg/Kg/hr BRL 52537 with continuous iv infusion starting 15 min prior to MCAO. In a second set of experiments, rats were treated with vehicle (saline), 1 mg/Kg/hr BRL 52537, 1 or 5 mg/Kg/hr norBNI starting at onset of reperfusion. All infusions were at a rate of 0.5 ml/hr and continued until the end of the experiment. Infarction volume was assessed by triphenyltetrazolium chloride (TTC) staining at 22 hr of reperfusion in all rats. TTC-determined infarction volume of ipsilateral caudoputamen (CP) complex in rats pretreated with BRL 52537 (N=7; 29±11 mm3; p<0.05) (mean±SEM) and cortex (61±32 mm3; p<0.05) was smaller than in rats treated with saline (N=7;72±4 mm3 and 174 ±24 mm3, respectively). Similarly, rats treated with BRL 52537 at the onset of reperfusion had smaller infarction volume in CP complex (N=10;35±9 mm3) and cortex (73±32 mm3) compared to saline (N=10;64±5 mm3 and 148±23 mm3, respectively). Rats treated with norBNI (N=10) at the onset of reperfusion had similar infraction volumes in the CP complex and the cortex as compared to saline controls. These data demonstrate that K-opioid receptor agonist provides significant neuroprotection when given as a pretreatment as well as following 2 hr of transient focal ischemia.