GPR37在神经病理性痛小鼠认知功能障碍中的作用

Role of GPR37 in cognitive dysfunction in a mouse model of neuropathic pain

目的评价G蛋白偶联受体37(GPR37)在神经病理性痛小鼠认知功能障碍中的作用。方法 SPF级健康雄性C57BL/6小鼠和GPR37基因敲除(GPR37-KO)小鼠, 3月龄, 体质量约20 g。采用随机数字表法分为4组(n=6):对照组(Con组)、神经病理性痛组(NPP组)、GPR37-KO+对照组(GPR37-KO Con组)和GPR37-KO+神经病理性痛组(GPR37-KO NPP组)。采用结扎坐骨神经的方法制备小鼠神经病理性痛模型, 术后7 d时测定热缩足潜伏期(TWL)和机械缩足反应阈(MWT), 术后28 d时行旷场实验和Morris水迷宫实验, 随后处死小鼠取内侧前额叶皮层(mPFC), 采用Western blot法检测磷酸化钙/钙调蛋白依赖性蛋白激酶Ⅱ(p-CAMKⅡ)水平、脑源性神经营养因子(BDNF)和突触后致密蛋白95(PSD-95)的表达。结果与Con组相比, GPR37-KO Con组小鼠各指标差异无统计学意义(P>0.05), NPP组小鼠TWL缩短, MWT降低, 旷场实验中央格停留时间延长, 穿越次数增加, Morris水迷宫实验逃避潜伏期延长, 穿越原平台位置次数减少, mPFC p-CAMKⅡ、BDNF和PSD-95表达下调(P<0.05);与NPP组相比, GPR37-KO NPP组小鼠TWL缩短, MWT降低, 旷场实验中央格停留时间延长, 穿越次数增加, Morris水迷宫实验逃避潜伏期延长, 穿越原平台位置次数减少, mPFC p-CAMKⅡ、BDNF和PSD-95表达下调(P<0.05)。结论 GPR37参与了神经病理性痛小鼠认知功能障碍形成的过程, 机制可能与其改变突触可塑性有关。

Objective To evaluate the role of G-protein coupled receptor 37(GPR37)in cognitive dysfunction in a mouse model of neuropathic pain.Methods SPF-grade healthy male C57BL/6 mice and GPR37 knockout(GPR37-KO)mice,aged 3 months,with a body weight of approximately 20 g,were divided into 4 groups(n=6 each)using a random number table method:control group(Con group),neuropathic pain group(NPP group),GPR37-KO+control group(GPR37-KO Con group)and GPR37-KO+neuropathic pain group(GPR37-KO NPP group).The mouse model of neuropathic pain was established by ligation of the sciatic nerve.The thermal paw withdrawal latency(TWL)and mechanical paw withdrawal threshold(MWT)were measured at 7 days after surgery.The open field test and Morris water maze test were performed at 28 days after surgery.The mice were subsequently sacrificed,and the medial prefrontal cortex(mPFC)was obtained for determination of the level of phosphorylated calcium/calmodulin-dependent protein kinaseⅡ(p-CAMKⅡ)and expression of brain-derived neurotrophic factor(BDNF)and postsynaptic density protein 95(PSD-95).Results Compared to Con group,no significant changes were found in the parameters in GPR37-KO Con group(P>0.05),and TWL was significantly shortened,MWT was decreased,the time the animal spent in central area was prolonged and the platform-crossing times were increased in the open field test,and the escape latency was prolonged and platform-crossing times were decreased in the Morris water maze test,and the expression of p-CAMKⅡ,BDNF and PSD-95 in the mPFC was down-regulated in NPP group(P<0.05).Compared with NPP group,TWL was significantly shortened,MWT was decreased,the time the animal spent in central area was prolonged and the platform-crossing times were increased in the open field test,and the escape latency was prolonged and platform-crossing times were decreased in the Morris water maze test,and the expression of p-CAMKⅡ,BDNF and PSD-95 in the mPFC was down-regulated in GPR37-KO NPP group(P<0.05).Conclusions GPR37 is involved in the development of cognitive dysfunction in mice with neuropathic pain,and the mechanism may be related to its modulation of synaptic plasticity.