瑞舒伐他汀部分恢复吗啡耐受大鼠的吗啡镇痛效能

目的探讨瑞舒伐他汀对吗啡耐受大鼠的吗啡镇痛效能的影响及其相关的分子机制。方法 48只♂SD大鼠随机分成6组(n=8):Ⅰ组为空白对照组;Ⅱ组为吗啡耐受组;Ⅲ组为10 mg.kg-1瑞舒伐他汀对照组;Ⅳ组、Ⅴ组、Ⅵ组分别为0.4、2、10 mg.kg-1瑞舒伐他汀处理组。Ⅱ、Ⅳ、Ⅴ、Ⅵ组皮下注射吗啡10 mg.kg-1,Ⅰ组和Ⅲ组皮下注射生理盐水,每天8∶00和16∶00各1次,连续10 d。d 6起,上午皮下注射前30 min,Ⅰ、Ⅱ组给予生理盐水灌胃,Ⅲ、Ⅳ、Ⅴ、Ⅵ组给予相应剂量的瑞舒伐他汀灌胃,连续5 d。d 6、11,测定大鼠基础热缩足潜伏期(PWTL)后,计算尾静脉注射吗啡30 min时各组大鼠的MPE值。d 11行为学检测后处死大鼠,留取腰5脊髓,比较各组脊髓内细胞外调节蛋白激酶(ERK)、磷酸化细胞外调节蛋白激酶(p-ERK)及星形胶质细胞表面标志物GFAP的表达水平。结果①d 6,6组的基础PWTL无明显差异。与Ⅰ组相比,Ⅱ、Ⅳ、Ⅴ和Ⅵ组MPE值明显降低(P<0.05)。d 11,6组的基础PWTL无差异。与Ⅰ组相比,Ⅱ、Ⅳ组尾静脉注射吗啡后30 min的MPE值明显降低(P<0.05);与Ⅱ组相比,Ⅴ、Ⅵ组的MPE值明显升高(P<0.05)。②d 11,6组大鼠腰5脊髓内总ERK表达水平差异无显著性。与Ⅰ组相比,Ⅱ、Ⅳ组腰5脊髓内p-ERK表达明显升高(P<0.05);与Ⅱ组相比,Ⅲ、Ⅴ、Ⅵ组腰5脊髓内p-ERK表达明显降低(P<0.05)。与Ⅰ组相比,Ⅱ组腰5脊髓内GFAP的荧光强度明显升高(P<0.05);与Ⅱ组相比,Ⅵ组腰5脊髓内GFAP的强度明显降低(P<0.05)。结论瑞舒伐他汀能够部分恢复吗啡耐受大鼠的吗啡镇痛效果,这可能与其抑制脊髓内ERK的磷酸化,减少星形胶质细胞活化有关。

Rosuvastatin partially restored the analgesic effect of morphine in rats with morphine tolerance

Aim To explore the effect of rosuvastatin on the analgesic effect of morphine in rats with morphine tolerance and investigate possible the underlying mechanisms.Methods Forty-eight male SD rats were randomly divided into six groups(n=8):saline control group(group Ⅰ),morphine tolerance group(group Ⅱ),10 mg·kg-1 rosuvastatin control group(group Ⅲ),0.4 mg·kg-1 rosuvastatin treatment group(group Ⅳ),2 mg·kg-1 rosuvastatin treatment group(groupⅤ) and 10 mg·kg-1 rosuvastatin treatment group(group Ⅵ).Rats were treated with subcutaneous injections of either saline(group Ⅰ,Ⅲ) or 10 mg·kg-1 morphine(group Ⅱ,Ⅳ,Ⅴ,Ⅵ).The injections were given twice daily at 8 ∶ 00 and 16 ∶ 00 for 10 days.The oral gavage of either saline(group Ⅰ,Ⅱ) or rosuvastatin(10,0.4,2,10 mg·kg-1 respectively for group Ⅲ,Ⅳ,Ⅴ,Ⅵ) began on day 6 and lasted for 5 consecutive days.Basic Paw withdrawal thermal latency(PWTL) was assessed on day 6 and 11,after that morphine(4 mg·kg-1) was injected via tail vein to determine the percentage of maximal possible effect(%MPE) 30min after the injection.Lumbar 5 spinal cord was obtained immediately after the behavioral tests to determine the expression of ERK and p-ERK.Results On day 6,the basic PWTL was similar among six groups.Compared with group Ⅰ,group Ⅱ,Ⅳ,Ⅴ and Ⅵ showed significant decrease of %MPE at 30min.On day 11,there was no significant difference in the basic PWTL among six groups.Compared with group Ⅰ,group Ⅱ and Ⅳ showed a significant difference in the decrease of %MPE at 30min.Compared with %MPE at 30min of group Ⅱ,group Ⅲ,Ⅴ and Ⅵ showed a significant difference increase.The expression of ERK in L5 spinal cord showed no significant difference among six groups.However,compared with group Ⅰ,the expression of p-ERK in group Ⅱ and Ⅳ was obviously increased.Compared with group Ⅱ,the expression of p-ERK in group Ⅲ,Ⅴ and Ⅵ was obviously decreased.Compared with group Ⅰ,the expression of GFAP in group Ⅱ was obviously increased,Compared with group Ⅱ,the expression of GFAP in group Ⅵ were obviously decreased.Conclusion Rosuvastatin partially restores the analgesic effect of morphine in rats with morphine tolerance possibly through inhibiting the phosphorylation of ERK and activation of astrocytes in the spinal cord.