mTOR信号通路参与神经病理性疼痛脊髓背角突触可塑性调节的机制
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摘要
目的：本研究结合行为学与形态学实验方法,通过观察大鼠痛阈变化规律和mTOR、AMPA受体亚基在大鼠脊髓背角浅层表达的变化,分析mTOR与AMPA受体亚基表达以及疼痛行为学改变的关系；采用鞘内注射mTOR特异性抑制剂雷帕霉素,观察雷帕霉素对CCI大鼠痛阈及其脊髓背角浅层AMPA受体亚基表达的影响,探讨mTOR参与神经病理性疼痛的机制。
方法：SD大鼠25只,随机分为5组,每组5只：(1)CCI模型组,分离结扎左侧坐骨神经；(2)手术对照组,分离暴露左侧坐骨神经,绕线不结扎；(3)雷帕霉素组,建立CCI模型,鞘内注射mTOR抑制剂雷帕霉素；(4)溶剂组,建立CCI模型,鞘内注射药物溶剂DMSO;(5)正常对照组,不做任何处理。分别测定各组大鼠的机械痛阈和热痛阈,取腰段脊髓分别做形态学观察,免疫组化观察脊髓背角浅层mTOR以及AMPA受体亚基表达。
结果：行为学结果显示：与正常对照组比较,CCI模型组术后1天PWMT和PWTL均出现显著下降(P<0.05),术后7天降到最低。与CCI模型组比较,溶剂组术后各时间点PWMT和PWTL差异无统计学意义(P>0.05),雷帕霉素组于手术后3天、5天和7天PWMT和PWTL显著升高(P<0.05),于第7天差异最明显。免疫组化结果显示：与正常对照组比较,CCI模型组、雷帕霉素组和溶剂组左侧脊髓背角浅层mTOR、AMPA受体亚基GluR1、GluR2表达明显增加(P<0.05)。与CCI模型组和溶剂组比较,雷帕霉素组mTOR以及AMPA受体表达明显减少(P<0.05)。mTOR与AMPA受体亚基GluR1、mTOR与GluR2在脊髓背角浅层共表达。
结论：mTOR。信号通路参与神经病理性疼痛的调节,雷帕霉素能有效抑制CCI大鼠的痛行为omTOR信号通路可能通过脊髓背角AMPA受体参与神经病理性疼痛的调节。
Object:In this study,we used the behavior and histology methods to test the pain thresholds of each rat,and to recorde the distribution of mTOR (mammalian target of rapamycin) and AMPA (a-amino-3-hydroxy-5- methylisoxazole-propionate) receptor subunits on the superficial lamella spinal dorsal horn of CCI (chronic constriction injury of the sciatic nerve) rats. In order to determining whether mTOR signaling pathway(s) play an important role during the maintence of neuropathic pain through AMPA receptors,we applicated mTOR special inhibitor rapamycin on CCI rats, and observed the changes of the pain thresholds and the distribution of AMPA receptor subunits.
Methods:Twenty-five rats were divided into five groups randomly. The rats in control group were normal rats. The rats in CCI group received an operation of ligation of left sciatic nerve. The rats in shame group received exposure of left sciatic nerve without ligation. The rats in Rapamycin group received intrathecal injection of Rapamycin after CCI.The rats in vehicle group received intrathecal injection of DMSO after CCI.
Results:There is no distinction between each group of rats'basic PWMT or PWTL (P>0.05) The rats in shame group and control group have no diversity in PWMT and PWTL test (P>0.05). Contrast to the rats in control group, the PWMT and PWTL of the rats in CCI group significantly attenuation (P<0.05).We also can see signification distinction of PWMT and PWTL between the rats in Rapamycin group and any other groups (P<0.05)。We used immunohistochemistry to show that mTOR and AMPA receptor subunits focuse on the spinal dorsal horn Ⅰ-Ⅲlamellar of rats.The quantity of mTOR and AMPA receptor subunits on rats after CCI was significantly higher than rats in control or shame group. Contrast to DMSO, Rapmycin was potent to reduce the quantity of mTOR and AMPA receptor subunits on spinal horn.Of rats' spinal horn superficial lamellar double-immunostained for glutamate receptor subunits and either marker for mTOR,a significantly large proportion co-express GluR1/2 and mTOR exists.
Conclusion:We can conclued that AMPA receptor subunits and mTOR involved in neuropathic pain. Rapmycin is effective to intercept nociception signals transmission and retard the proceduce of neuropathic pain. These observations support the idea that AMPA receptors involved in neuropathic pain,may be modulated by mTOR signaling pathway(s).
方法：SD大鼠25只,随机分为5组,每组5只：(1)CCI模型组,分离结扎左侧坐骨神经；(2)手术对照组,分离暴露左侧坐骨神经,绕线不结扎；(3)雷帕霉素组,建立CCI模型,鞘内注射mTOR抑制剂雷帕霉素；(4)溶剂组,建立CCI模型,鞘内注射药物溶剂DMSO;(5)正常对照组,不做任何处理。分别测定各组大鼠的机械痛阈和热痛阈,取腰段脊髓分别做形态学观察,免疫组化观察脊髓背角浅层mTOR以及AMPA受体亚基表达。
结果：行为学结果显示：与正常对照组比较,CCI模型组术后1天PWMT和PWTL均出现显著下降(P<0.05),术后7天降到最低。与CCI模型组比较,溶剂组术后各时间点PWMT和PWTL差异无统计学意义(P>0.05),雷帕霉素组于手术后3天、5天和7天PWMT和PWTL显著升高(P<0.05),于第7天差异最明显。免疫组化结果显示：与正常对照组比较,CCI模型组、雷帕霉素组和溶剂组左侧脊髓背角浅层mTOR、AMPA受体亚基GluR1、GluR2表达明显增加(P<0.05)。与CCI模型组和溶剂组比较,雷帕霉素组mTOR以及AMPA受体表达明显减少(P<0.05)。mTOR与AMPA受体亚基GluR1、mTOR与GluR2在脊髓背角浅层共表达。
结论：mTOR。信号通路参与神经病理性疼痛的调节,雷帕霉素能有效抑制CCI大鼠的痛行为omTOR信号通路可能通过脊髓背角AMPA受体参与神经病理性疼痛的调节。
Object:In this study,we used the behavior and histology methods to test the pain thresholds of each rat,and to recorde the distribution of mTOR (mammalian target of rapamycin) and AMPA (a-amino-3-hydroxy-5- methylisoxazole-propionate) receptor subunits on the superficial lamella spinal dorsal horn of CCI (chronic constriction injury of the sciatic nerve) rats. In order to determining whether mTOR signaling pathway(s) play an important role during the maintence of neuropathic pain through AMPA receptors,we applicated mTOR special inhibitor rapamycin on CCI rats, and observed the changes of the pain thresholds and the distribution of AMPA receptor subunits.
Methods:Twenty-five rats were divided into five groups randomly. The rats in control group were normal rats. The rats in CCI group received an operation of ligation of left sciatic nerve. The rats in shame group received exposure of left sciatic nerve without ligation. The rats in Rapamycin group received intrathecal injection of Rapamycin after CCI.The rats in vehicle group received intrathecal injection of DMSO after CCI.
Results:There is no distinction between each group of rats'basic PWMT or PWTL (P>0.05) The rats in shame group and control group have no diversity in PWMT and PWTL test (P>0.05). Contrast to the rats in control group, the PWMT and PWTL of the rats in CCI group significantly attenuation (P<0.05).We also can see signification distinction of PWMT and PWTL between the rats in Rapamycin group and any other groups (P<0.05)。We used immunohistochemistry to show that mTOR and AMPA receptor subunits focuse on the spinal dorsal horn Ⅰ-Ⅲlamellar of rats.The quantity of mTOR and AMPA receptor subunits on rats after CCI was significantly higher than rats in control or shame group. Contrast to DMSO, Rapmycin was potent to reduce the quantity of mTOR and AMPA receptor subunits on spinal horn.Of rats' spinal horn superficial lamellar double-immunostained for glutamate receptor subunits and either marker for mTOR,a significantly large proportion co-express GluR1/2 and mTOR exists.
Conclusion:We can conclued that AMPA receptor subunits and mTOR involved in neuropathic pain. Rapmycin is effective to intercept nociception signals transmission and retard the proceduce of neuropathic pain. These observations support the idea that AMPA receptors involved in neuropathic pain,may be modulated by mTOR signaling pathway(s).
引文
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