μ、κ阿片受体激动剂对老年大鼠术后认知功能及海马TLR4表达的影响

目的研究μ、κ阿片受体激动剂对老年大鼠术后认知功能及海马Toll样受体4（TLR4）表达的影响。方法64只健康清洁级老年雄性大鼠，按照排除标准剔除4只，纳入60只大鼠随机分为3组，每组各20只。予以各组大鼠异氟醚麻醉下剖腹探查术，随后μ阿片受体激动剂组大鼠尾静脉输注DAMGO 0.2 mg/h，κ阿片受体激动剂组大鼠尾静脉输注U50，488H 0.05 mg/h，对照组大鼠尾静脉输注等量生理盐水。应用Y迷宫实验测试大鼠的认知功能，观察记录大鼠的游泳速度、逃避潜伏期、穿越平台次数、停留时长、游泳距离。分别在输注前、输注后6 h、12 h、1 d、3 d进行神经功能缺损评分（NSS）。行为学检测结束后处死大鼠，取海马组织，用酶联免疫吸附法检测大鼠海马组织的TLR4表达水平及白细胞介素-1（IL-1）、肿瘤坏死因子-α（TNF-α）、中枢神经特异性蛋白（S100β蛋白）、神经元特异性烯醇化酶（NSE）的含量。结果3组大鼠海马组织的IL-1、TNF-α、TLR4、S100β蛋白、NSE水平间存在显著差异（P＜0.05~0.001），其中μ阿片受体激动剂组的各项指标均明显低于其他两组（均P＜0.05）。3组大鼠Y迷宫实验中的游泳速度、逃避潜伏期、穿越平台次数、停留时间、游泳距离间存在显著差异（P＜0.05~0.001），其中μ阿片受体激动剂组的各项指标均优于其他两组（均P＜0.05）。3组大鼠输注前的NSS评分比较，差异无统计学意义（P＞0.05）。3组大鼠输注后6 h、12 h、1 d、3 d的NSS评分均显著低于输注前（均P＜0.001），其中μ阿片受体激动剂组输注后各时间点的NSS评分均显著低于其他两组（均P＜0.05）。结论μ、κ阿片受体激动剂能有效地改善老年大鼠的术后认知功能，尤其是μ阿片受体激动剂，同时能显著抑制海马组织的TLR4表达，促进海马区域炎症反应消退。

Abstract: Objective To study the effects of μ, κ opioid receptor agonists on postoperative cognitive function and the expression of Toll like receptor 4(TLR4) in hippocampus of elderly rats. Methods 64 healthy and clean aged male rats were excluded according to the exclusion criteria, and 60 rats were included. They were randomly divided into 3 groups with 20 rats in each group. Rats in each group were performed laparotomy under isoflurane anesthesia. DAMGO was infused into caudal vein 0.2 mg/h in μ opioid receptor agonist group. U50， 488H was injected into tail vein 0.05 mg/h in κ opioid receptor agonist group. Rats in the control group were infused with the same amount of normal saline through caudal vein. Y maze experiment was used to test the cognitive function of rats. The swimming speed, escape latency, times of crossing the platform, length of stay and swimming distance were observed and recorded.Neurological deficit score(NSS) was performed before infusion, 6 h, 12 h, 1 d and 3 d after infusion.After the behavioral test, the rats were killed, and the hippocampal tissue was taken. The expression level of TLR4, interleukin-1(IL-1) and tumor necrosis factor were detected by tumor necrosis factor-α（TNF- α）, central nervous system soluble protein-100β(S100β), neuron-specific enolase(NSE). Results There were significant differences in the levels of IL-1, TNF-α, TLR4, S100β protein and NSE in the hippocampus of the three groups(P<0.05~0.001). There were significant differences in swimming speed, escape latency, times of crossing the platform, residence time and swimming distance among the three groups(P<0.05~0.001). Among them, the indexes of μ opioid receptor agonist group were better than those of the other two groups(all P<0.05). There was no significant difference in NSS scores between the three groups before infusion(P>0.05). The NSS scores at 6 h, 12 h, 1 d and 3 d after infusion in the three groups were significantly lower than those before infusion(all P<0.001), and the NSS scores at each time point after infusion in the μ opioid receptor agonist group were significantly lower than those in the other two groups(all P<0.05). Conclusions μ, κ opioid receptor agonists can effectively improve the postoperative cognitive function of elderly rats, especially μ opioid receptor agonists. At the same time, they can significantly inhibit the expression of TLR4 in hippocampus and promote the regression of inflammatory response in hippocampus.