The signaling pathway of chronic morphine treatment to prevent neuronal damage following transient cerebral ischemia is not clear. In the present study, we examined the role of mammalian target of rapamycin (mTOR) to reveal the neuroprotective effects of chronic morphine preconditioning on the hippocampus following ischemia/reperfusion (I/R) injury. Morphine was administrated for 5 days twice a day before I/R injury induction. The possible role of mTOR was evaluated by the injection of

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... (5 mg/kg, ip) before I/R injury induction. The passive avoidance test was used to evaluate memory performance. Neuronal density and apoptosis were measured in the CA1 region, 72 hours after the induction of I/R injury. The expressions of mTOR and phosphorylated mTOR (p-mTOR) and superoxide dismutase (SOD) activity were determined 24 hours after I/R injury induction. Chronic morphine treatment attenuated the apoptosis and neuronal loss in the hippocampus after I/R injury, which led to improvement in memory (P < 0.05 vs I/R) and increase in the expression of p-mTOR (P < 0.05 vs I/R) and SOD activity (P < 0.05 vs I/R) in the hippocampus. Pretreatment with rapamycin abolished all the above-mentioned protective effects. These results describe novel findings whereby chronic morphine preconditioning in hippocampal CA1 neurons is mediated by the mTOR pathway and through increased phosphorylation of mTOR can improve oxidative stress and apoptotic agents and eventually protect the hippocampus against I/R injury.