Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsol...Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.展开更多
目的探讨异氟烷预处理抗脑缺血再灌注损伤过程中蛋白激酶γ(gamma of protein kinase C,PKCγ)在细胞膜和细胞浆内转位中的动态变化规律。方法采用大脑中动脉线拴方法制备大鼠局灶性脑缺血再灌注模型。72只SD大鼠随机分为3组:假手术组24...目的探讨异氟烷预处理抗脑缺血再灌注损伤过程中蛋白激酶γ(gamma of protein kinase C,PKCγ)在细胞膜和细胞浆内转位中的动态变化规律。方法采用大脑中动脉线拴方法制备大鼠局灶性脑缺血再灌注模型。72只SD大鼠随机分为3组:假手术组24只,根据再灌注后各时间点不同又分为再灌注后4、24、72 h组,每组8只。缺血再灌注组、异氟烷预处理组,每组24只,根据缺血再灌注后时间点不同又分为缺血再灌注后4、24、72 h组,每组8只。假手术组分别在再灌注后4、24、72 h处死大鼠,取大鼠额叶皮质;缺血再灌注组大鼠前脑缺血2 h后,分别在再灌注后4、24、72 h处死大鼠,取大脑额叶皮质;异氟烷预处理组于缺血前1.5 h经半密闭的吸入箱吸入1.5%异氟烷,持续1、0.5 h后制备脑缺血再灌注模型,其余同缺血再灌注组。各亚组大鼠大脑额叶皮质细胞浆和细胞膜上的PKCγ含量用免疫印迹(Western blot)法测定。结果与假手术组的再灌注后4、24、72 h组比较,缺血再灌注组和异氟烷预处理组的同时间点组细胞膜上PKCγ水平均有显著升高(P均<0.05)、在细胞浆中的PKCγ水平均有显著减少(P均<0.05)。异氟烷预处理组的缺血再灌注后4、247、2 h组PKCγ水平均较缺血再灌注组的同时间点组在细胞膜上显著升高(P均<0.05)、在细胞浆中的PKCγ水平均有显著减少(P均<0.05),且异氟烷预处理组的缺血再灌注后24 h组PKCγ水平为最高。结论异氟烷预处理可增加大鼠大脑额叶皮质PKCγ向细胞膜转位;PKCγ膜转位可能有利于大鼠脑的缺血再灌注损伤。展开更多
基金supported by the National Natural Science Foundation of China(81971058,82371226,82101295,82301398)the National Funded Postdoctoral Researcher Program(GZC20233585)The Boost Plan of Xijing Hospital(XJZT24QN25,XJZT25CX22).
文摘Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.
