血管紧张素Ⅱ受体拮抗剂EMA401作用于神经病理性疼痛模型大鼠的行为学评估及镇痛效应机制

Angiotensin Ⅱ receptor antagonist EMA401 used for sciatic nerve constriction-induced neuropathic pain in rats: behavior assessment and analgesic mechanisms

背景:慢性疼痛的发病率高,病程长,治疗效果差,疼痛的发病机制未完全明确,镇痛药物的研究及镇痛机制的探索是目前研究的热点。目的:研究血管紧张素Ⅱ受体拮抗剂EMA401对大鼠坐骨神经缩窄致神经病理性疼痛模型机械缩足阈的影响及可能的作用机制。方法:SD大鼠随机分为5组,假手术组只暴露坐骨神经,不做任何结扎;其余各组均建立坐骨神经缩窄模型。根据EMA401灌胃剂量分为2 mg/kg,5 mg/kg,10 mg/kg组,假手术组和模型对照组大鼠每天灌胃NaC l溶液。在术前1 d及术后3,7,14 d,检测各组大鼠机械缩足阈行为学指标;行为学检测完毕后取各组大鼠取脊髓背根神经节,采用Western Blotting法检测胶质纤维酸性蛋白、脑源性神经营养因子、活化转录因子3的表达。结果与结论:(1)与模型对照组相比,EMA401可提高坐骨神经缩窄大鼠机械缩足反射阈值(P<0.05);(2)与模型对照组相比,EMA401可降低背根神经节内胶质纤维酸性蛋白、脑源性神经营养因子、活化转录因子3表达(P<0.05),与2 mg/kg EMA401组相比,5 mg/kg,10 mg/kg EMA401组术后3,7,14 d胶质纤维酸性蛋白、脑源性神经营养因子、活化转录因子3表达量均显著降低(P<0.05);(3)结果表明,EMA401对坐骨神经缩窄模型大鼠有明显的镇痛效应,其机制可能与抑制脊髓背根神经节内星形胶质细胞活化,降低脑源性神经营养因子表达,进而抑制以活化转录因子3表达增多为特点的背根神经节神经元活化有关。

BACKGROUND:Chronic pain is characterized as high morbidity,long course and poor curative efficacy,and the underlying mechanism still remains unclear.The research on analgesics and analgesic mechanisms is an issue of concern.OBJECTIVE:To explore the effect of angiotensin II receptor antagonists EMA401 on the mechanical withdrawal threshold in a rat model of sciatic nerve constriction-induced neuropathic pain and the underlying mechanisms.METHODS:Sprague-Dawley rats were randomized into five groups:the rat sciatic nerve was exposed without ligation(sham group),and NaCl solution was given via gastric lavage;the model of sciatic nerve constriction was established in the remaining rats,followed by treatment with 2,5 and 10 mg/kg EMA401,and NaCl solutions(model group)via gastric lavage,respectively.As a behavioral indicator,mechanical withdrawal threshold was detected at 1 preoperative day,3,7 and 14 postoperative days.Subsequently,the spinal dorsal root ganglion was removed,and the expression levels of glial fibrillary acidic protein,brain-derived neurotrophic factor and activating transcription factor 3 were detected by western blot assay.RESULTS AND CONCLUSION:Compared with the model group,EMA401 significantly improved the mechanical withdrawal threshold of the rats with sciatic nerve constriction(P<0.05).Moreover,EMA401 significantly upregulated the expression levels of glial fibrillary acidic protein,brain-derived neurotrophic factor and activating transcription factor 3 in the dorsal root ganglion(P<0.05);the expression levels in the 5 and 10 mg/kg EMA401 groups were significantly lower than those in the 2 mg/kg EMA401 group at 3,7 and 14 days postoperatively(P<0.05).These findings implicate that EMA401 exerts obvious analgesic effect on the rat model of sciatic nerve constriction,which may be via inhibiting astrocyte activation in the spinal dorsal root ganglion,downregulating the expression level of brain-derived neurotrophic factor,and further inhibiting the dorsal root ganglion neuron activation that appears with an increase in activated transcription factor 3 expression.