人参皂苷Rd通过中枢γ-氨基丁酸能神经对神经病理性疼痛的镇痛作用机制  

Ginsenoside Rd relieves neuropathic pain by regulating GABA neurons in brain and spinal cord of mice

作　　者：成帆 崔旭鑫 石磊[2] 高进贤[2] 杨孝来 CHENG Fan;CUI Xu-xin;SHI Lei;GAO Jin-xian;YANG Xiao-lai(School of Pharmacy,Gansu University of Chinese Medicine,Lanzhou 730000,China;Dept of Pharmacy,Gansu Provincial Hospital,Lanzhou 730000,China)

机构地区：[1]甘肃中医药大学药学院,甘肃兰州730000 [2]甘肃省人民医院药剂科,甘肃兰州730000

出　　处：《中国药理学通报》2024年第11期2141-2149,共9页Chinese Pharmacological Bulletin

基　　金：甘肃省科学技术厅自然科学基金(No 20JR10RA383,23JRRA1773);甘肃省人民医院院内科研基金(No 20GSSY4-26)。

摘　　要：目的探讨人参皂苷Rd(ginsenoside Rd,GSRd)对小鼠坐骨神经分支选择性损伤(spared nerve injury,SNI)所致神经病理性疼痛(neuropathic pain,NP)的镇痛作用及机制。方法建立SNI模型,检测行为学指标验证模型稳定性、GSRd对SNI所致神经痛的镇痛作用。GSRd与γ-氨基丁酸(gamma aminobutyric acid,GABA)系统工具药联用,分析GSRd治疗SNI所致神经痛与GABA能神经的关系。免疫荧光染色观察SNI所致神经痛小鼠腹外侧视前核(ventrolateral preoptic nucleus,VLPO)、中脑导水管周围灰质腹外侧区(ventrolateral periaqueductal gray,VLPAG)和脊髓背角(spinal dorsal horn,SDH)中c-Fos、c-Fos与GAT-1免疫阳性细胞共表达情况,分析GSRd镇痛作用与痛觉传导通路核团及核团神经元的关系。结果SNI神经痛小鼠术后第3天开始痛阈变化、产生痛敏,可持续至少14 d;GSRd 500、1000 mg·kg^(-1)使SNI所致神经痛小鼠痛阈升高。GABA系统工具药能协同或拮抗GSRd对SNI所致神经痛小鼠的镇痛作用;SNI所致神经痛小鼠VLPO、VLPAG和SDH的c-Fos免疫阳性细胞增加,GSRd 500 mg·kg^(-1)可减少SNI所致神经痛小鼠VLPO、VLPAG和SDH的c-Fos与GAT-1共表达免疫阳性细胞。结论SNI所致神经痛模型稳定,GSRd具有明显的镇痛作用,机制与下调VLPO、VLPAG、SDH中的GAT-1,减少其对突触间隙GABA的重摄取,增强中枢GABA能神经的抑制作用相关。Aim To investigate the analgesic effect of ginsenoside Rd(GSRd)on spared nerve injury(SNI)induced neuropathic pain(NP)in mice and the underlying mechanism.Methods SNI model was established and behavioral indexes were tested to verify the stability of the model and the analgesic effect of GSRd on neuralgia induced by SNI.The relationship between SNI-induced neuralgia and GABaergic nerve was analyzed by GSRd in combination with gamma-aminobutyric acid(GABA)system tool.Immunofluorescence staining was used to observe ventrolateral preoptic nucleus(VLPO)and ventrolateral periaqueductal gray in rats with neuralgia induced by SNI.The expression of c-Fos,c-Fos and GAT-1 immunopositive cells in VLPAG and SDH were analyzed.The relationship between the analgesic effect of GSRd and the nuclear group and nuclear group neurons of pain transduction pathway was analyzed.Results The pain threshold of SNI neuralgia mice began to change on the 3rd day after operation,and pain sensitivity was produced,which lasted for at least 14 days.GSRd 500 or 1000 mg·kg^(-1) increased the pain threshold of SNI-induced neuralgia mice.GABA system tool drug could coordinate or antagonize the therapeutic effect of GSRd on neuralgia induced by SNI in mice.The c-Fos immunopositive cells of VLPO,VLPAG and SDH revealed a notable increase in SNI mice,and GSRd 500 mg·kg^(-1) could reduce the number of c-Fos and GAT-1 co-expressing immunopositive cells in VLPO,VLPAG and SDH mice induced by SNI.Conclusions The neuralgia model induced by SNI is stable,and GSRd has significant analgesic effect.The mechanism involves down-regulating GAT-1 in VLPO,VLPAG and SDH to reduce its reuptake of GABA in the synaptic gap,thereby enhancing the inhibitory effect of central GABaergic nerve.

关 键 词：人参皂苷RD 神经病理性疼痛 Γ-氨基丁酸 腹外侧视前核 中脑导水管周围灰质腹外侧区 脊髓背角 

分 类 号：R285.5[医药卫生—中药学]