Cerebroprotective Effect of Nociceptin on Transient Focal Cerebral Ischemia in Rats

This study aimed to investigate the cerebroprotective effect of nociceptin on transient focal cerebral ischemia in Sprague-Dawley rats by determining the changes in regional cerebral blood flow (rCBF) and the infarct size. Right middle cerebral artery (MCA) was occluded for 2 hours, and thereafter was followed by reperfusion by an intraluminal monofilament technique. An open cranial window was made on the right parietal bone for determination of continuous changes in rCBF by laser-Doppler flowmetry. The infarct size was morphometrically determined using the 2,3,5-triphenyltetrazolium chloride technique. In normal rats, nociceptin ($0.01\~100\;nmol/kg$, Lv.) increased rCBF and decreased cerebral arterial resistance in a dose-dependent manner. Systemic arterial blood pressure was little affected by nociceptin at the doses of 0.01 and 0.1nmol/kg, but dose-dependently reduced at the doses of 1 nmol/kg or more. In transient cerebral ischemic rats, nociceptin ($0.01\~0.1$ nmol/kg, i.p.) significantly attenuated the postischemic cerebral hyperemia, and progressively increased rCBF. The improving effect of nociceptin on the postischemic rCBF response was markedly blocked by pretreatment with $[Nphe^1]nociceptin(1-13)NH_2$ (1 nmol/kg, i.p.), a selective nociceptin receptor antagonist, but not by naloxone ($3{\mu}mol/kg$, i.p.), a selective opioid receptor antagonist. The cerebral infarct size was significantly reduced by nociceptin ($0.01\~0.1$ nmol/kg) administered i.p. 5 min after MCA occlusion in transient cerebral ischemia of 2-hour MCA occlusion and 22-hour reperfusiion. It is suggested that nociceptin improves the postischemic cerebral hemodynamics and thereby has a cerebroprotective effect in transient focal cerebral ischemia.