BACKGROUND: Ephedrine promotes neural plasticity in rats following cerebral iscbemia/reperfusion injury. Ephedrine has been combined with naloxone in some studies, and it has been confirmed that their combination has synergistic effects on increasing neural plasticity following cerebral ischemia/reperfusion injury.OBJECTIVE: To investigate the effects of ephedrine combined with various doses of naloxone on neural plasticity and to find an optimal dose of naloxone in rats after cerebral ischemia/reperfusion injury by analyzing growth associated protein-43 (GAP-43), synaptophysin and β -endorphin expression in the hippocampal CA3 area.DESIGN, TIME AND SETTING: This immunohistochemical, randomized, controlled, animal experiment was performed at the Chongqing Research Institute of Pediatrics, China from September 2007 to June 2008.MATERIALS: Ephedrine hydrochloride injection and naloxone hydrochloride injection were respectively purchased from Shandong Lvliang Pharmaceutical Factory, China and Sichuan Jingwei Pharmaceutical Co.,Ltd., China. A total of 192 healthy adult Sprague Dawley rats were used to establish models of left middle cerebral artery occlusion using the suture occlusion method.METHODS: At 2 hours following cerebral ischemia, the rats were intraperitoneally injected with 1.5 mg/kg/d ephedrine (ephedrine group), with 0.1, 0.2, or 0.3 mg/kg/d naloxone (low, moderate and high doses of naloxone groups), with 1.5 mg/kg/d ephedrine + 0. 1, 0.2, or 0.3 mg/kg/d naloxone (ephedrine + low,moderate and high doses of naloxone groups), and with 0.5 mL saline (model group), respectively.MAIN OUTCOME MEASURES: GAP-43, synaptophysin and β -endorphin expression were detected in the hippocampal CA3 area using immunohistochemistry 1-4 weeks after surgery. Sensorimotor integration in rats was assessed using the beam walking test.RESULTS: GAP-43 and synaptophysin expression was greater in the ephedrine group, and in the ephedrine + moderate and high doses of naloxone groups compared with the model group. GAP-43 and synaptophysin expression was greatest in the ephedrine + high dose of naloxone group at 2 and 3 weeks after surgery. β -endorphin expression was significantly lower in the ephedrine group, and in the ephedrine + moderate and high doses of naloxone groups compared with the model group (P < 0.05). β -endorphin expression was persistently low in the ephedrine + high dose of naloxone group. At 1-3 weeks after surgery,the beam walking test score was significantly higher in the ephedrine group and ephedrine + various doses of naloxone groups than in the model group (P < 0.05). The score was higher in the ephedrine + moderate and high doses of naloxone groups than in the ephedrine group (P < 0.05). Moreover, the score was increased as the dose of naloxone increased in the ephedrine + various doses of naloxone groups.CONCLUSION: Ephedrine promotes GAP-43 and synaptophysin expression, inhibits β -endorphin expression in the hippocampal CA3 area, and improves motor function in rats following cerebral ischemia/reperfusion injury. Naloxone does not have the above-mentioned effects. During combined treatment with ephedrine and naloxone, however, the above-described effects are enhanced with an increased dose of naloxone. The combination of ephedrine ( 1.5 mg/kg/d) and naloxone (0,3 mg/kg/d) can produce optimal therapeutic efficacy in treatment of cerebral ischemic injury.