CGRP和IB4（+）C纤维在神经病理性疼痛阳—阴性症状中的作用
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摘要
目的
神经病理性疼痛的外在表现既包含以痛觉过敏为特点的阳性症状也可能伴随以痛觉减退为特点的阴性症状,而同时伴随不同种类的阳性和阴性症状的神经病理性疼痛最为常见。探索可能导致不同症状的神经病理改变,是完善神经病理性疼痛发病机制并进行针对性治疗的必要条件。本研究采用应用不同的压力一过性挤压大鼠坐骨神经,构建复合神经病理性疼痛阳性和阴性症状的动物模型,并与经典的坐骨神经慢性缩窄伤(CCI)模型作对比。系统评估这两个模型大鼠热痛觉、冷痛觉、静态和动态机械痛觉以及疼痛相关行为等神经病理性疼痛表现,并分析外周传入神经纤维,背根神经节及其脊髓背角投射这一神经传导通路上IB4和CGRP的表达变化,探索CGRP和IB4免疫阳性神经传导通路对大鼠神经病理性疼痛阳性或阴性症状的不同调节作用。
方法
1.体重200-250g成年雄性SD大鼠24只,随机分为4组：Sham(n=6)、100g组(n=6)、400g组(n=6)和CCI组(n=6)。Sham组仅暴露左侧坐骨神经而不结扎,100g组和400g组分别以100g和400g的压力压迫大鼠坐骨神经3*10s,CCI组建立左侧CCI模型,术前1天及术后3、7、10、14、21、28天分别测定左足内外侧及右足内外侧机械痛阈和热痛阈和并对左右足的冷痛觉,动态触觉及自噬行为和疼痛行为等进行评价,术后3、10、21、28天分批灌注处死,取左侧坐骨神经、左侧腰5背根节及腰膨大处脊髓,多聚甲醛固定过夜。
2.取以上4组大鼠3、10、21、28天腰5背根节,OCT包埋,取200微米、250微米、300微米处切面,行双标免疫荧光染色,计算背根节中阳性细胞个数,比较各时间点不同组之间的阳性细胞数差异。取以上4组大鼠3、10、21、28天腰膨大处脊髓(约L4、L5节段),OCT包埋后行双标免疫荧光染色,计算同侧及对侧板层Ⅱ内IB4纤维面积及CGRP纤维面积。取以上4组大鼠10天坐骨神经,行波蒂安银染,比较4组神经纤维密度。
结果
1.与DO天相比,100g组和CCI组先后出现了热痛和机械痛的痛觉过敏(P<0.05),冷痛觉、动态触觉和疼痛相关行为的评分也较DO天增高。与100g组和CCI组相反,400g组出现了明显的痛觉减退,表现为热痛阈和机械痛阈升高(P<0.05),尽管冷痛觉、动态触觉和疼痛相关行为的评分也一定程度的升高,但重触觉的变化却没有统计学意义(P>0.05)。
2.在背根节中,与Sham组相比,100g组和CCI组的IB4和CGRP阳性细胞数出现了短暂的减少,而400g的IB4和CGRP阳性细胞数出现了持久的、难以恢复的减少。在脊髓当中,与对侧相比,100g组、400g和CCI组腰膨大板层Ⅱ中的IB4纤维均出现了减少,但只有400g组的CGRP纤维出现了明显的减少(P<0.05),而100g组和CCI组的CGRP纤维面积没有出现变化。在坐骨神经中,波蒂安银染显示400g组第10天的神经纤维明显较另外两组和sham组稀疏。
结论
1.100g压力一过性挤压大鼠坐骨神经产生与CCI类似的神经病理性疼痛阳性症状；400g压力除了导致冷痛觉和动态触觉过敏外,大鼠同时出现以热痛觉和机械性痛觉减退为表现的阴性症状。
2.比较不同组之间DRG和脊髓中IB4和CGRP阳性细胞和神经纤维的动态变化进行分析,IB4神经细胞可能参与疼痛信号的中枢调控,而CGRP直接传递热痛等疼痛信号。
Objectives
Hypoalgesia denotes a decreased or increased threshold to thermal, cold or mechanical stimuli. Hypoalgesia occurs after nerve injury, diabetes mellitus or other central or peripheral neuropathies, which accompany with positive or negative sign of neuropathic pain. In our experiment, negative and positive signs are induced by crushing the rat scaitic nerve with different pressures measured by FSR sensor. Furthermore, DRG and spine immunofluerescence staining showed that transient loss of IB4positive non-peptidergic C fiber occurred in the CCI and light crush groups with signs of hyperalgesia, while longer loss of CGRP positive peptidergic C fiber occurred in the heavy crush group with signs of hypoalgesia. The different phenotype indicated that these two kinds of C fiber had distinct functions in the pain signaling pathways: thermal hypoalgesia after nerve injury was resulted by the loss of peptidergic C fiber; non peptidergic C fiber played an important role in the central modulation of pain signaling and the onset of positive signs. These data provided new insights into the comprehensive therapy of neuropathic pain.
Methods
1. Twenty four male SD rats were randomly divided into four group Sham (n=6),100g (n=6),400g(n=6)and group CCI (n=6). In group CCI, left sciatic nerve CCI model were established according to Bennett and Xie, in group Sham, left sciatic nerves were only exposed without ligation. In100g group and400g group, left sciatic nerves were crushed by100g and400g force respectively. Paw withdrawal threshold to mechanical stimuli(MWT) and paw withdrawal latency to a thermal nociceptive stimulus(TWL) were measured at1day before (baseline) and3,7,10,14,21,28days after operation in the lateral and medial part of both left and right paw. Evaluation of the cold allodynia, touch allodynia and pain-related behavior were performed at1day before (baseline) and3,7,10,14,21,28days after operation in both left and right paw. The animals were then sacrificed and the left sciatic nerve, L5DRG and lumbar enlargement of the spinal cord were harvested at7,10,21,28days after operation and immersed in4%formaldehyde for a night.
2. The harvested DRG and Spine were embedded with OCT and stained with double labeling immunofluorescence method. In DRG, the segments at200micron,250micron and300micron were chose to calculate positive cells. In Spine, the area of positive nerve sprouting in ipilateral and contralateral lamina2were calculated. The sciatic nerve were performed with bodian silver staining method and the fiber density were compared in four group.
Results
1. Compared to DO, both the100g group and CCI groups showed thermal and mechanical hyperalgesia (P<0.05), and the behavior test scores of dynamic allodynia, cold allodynia and pain-related behavior were higher than DO. On the contrary, the400g group showed obvious hypoalgesia, which presented as higher thresholds of thermal and mechanical pain (P<0.05). Although there were a slight increase of the behavior test scores on dynamic allodynia, cold allodynia and pain-related beavior, but without statistical significance.
2. In dorsal root ganglion (DRG), compared to the Sham group, the number of IB4and CGRP positive neurons showed temporary decrease in the100g group and CCI group, while presented as long lasting, unrestorable decrease in the400g group. In spinal cord, the decrease of IB4fibers in Lamina2of the lumbar enlargement comparing to the contra side was shown in all of the100g,400g and CCI groups, while the decrease of CGRP fibers was only detected in the400g group (P<0.05). In sciatic nerves, Bodian Silver Staining showed that the density of fibers on D3in the400g group was lower comparing with that in the other two groups.
Conclusions
1、100g crush generated a transient pressure on rat sciatic nerve, led to signs of hyperalgesia that similar to CCI model.400crush resulted to cold and touch allodynia, as well as negative signs presented as mechanical and heat hypoalgesia
2、Compare the dynamic changes of IB4and CGRP positive neurons and fibers in DRG and spinal cord between groups, IB4fibers may take part in the central regulatory mechanisms of pain signaling, while CGRP fibers directly transduct the thermal pain signal.
神经病理性疼痛的外在表现既包含以痛觉过敏为特点的阳性症状也可能伴随以痛觉减退为特点的阴性症状,而同时伴随不同种类的阳性和阴性症状的神经病理性疼痛最为常见。探索可能导致不同症状的神经病理改变,是完善神经病理性疼痛发病机制并进行针对性治疗的必要条件。本研究采用应用不同的压力一过性挤压大鼠坐骨神经,构建复合神经病理性疼痛阳性和阴性症状的动物模型,并与经典的坐骨神经慢性缩窄伤(CCI)模型作对比。系统评估这两个模型大鼠热痛觉、冷痛觉、静态和动态机械痛觉以及疼痛相关行为等神经病理性疼痛表现,并分析外周传入神经纤维,背根神经节及其脊髓背角投射这一神经传导通路上IB4和CGRP的表达变化,探索CGRP和IB4免疫阳性神经传导通路对大鼠神经病理性疼痛阳性或阴性症状的不同调节作用。
方法
1.体重200-250g成年雄性SD大鼠24只,随机分为4组：Sham(n=6)、100g组(n=6)、400g组(n=6)和CCI组(n=6)。Sham组仅暴露左侧坐骨神经而不结扎,100g组和400g组分别以100g和400g的压力压迫大鼠坐骨神经3*10s,CCI组建立左侧CCI模型,术前1天及术后3、7、10、14、21、28天分别测定左足内外侧及右足内外侧机械痛阈和热痛阈和并对左右足的冷痛觉,动态触觉及自噬行为和疼痛行为等进行评价,术后3、10、21、28天分批灌注处死,取左侧坐骨神经、左侧腰5背根节及腰膨大处脊髓,多聚甲醛固定过夜。
2.取以上4组大鼠3、10、21、28天腰5背根节,OCT包埋,取200微米、250微米、300微米处切面,行双标免疫荧光染色,计算背根节中阳性细胞个数,比较各时间点不同组之间的阳性细胞数差异。取以上4组大鼠3、10、21、28天腰膨大处脊髓(约L4、L5节段),OCT包埋后行双标免疫荧光染色,计算同侧及对侧板层Ⅱ内IB4纤维面积及CGRP纤维面积。取以上4组大鼠10天坐骨神经,行波蒂安银染,比较4组神经纤维密度。
结果
1.与DO天相比,100g组和CCI组先后出现了热痛和机械痛的痛觉过敏(P<0.05),冷痛觉、动态触觉和疼痛相关行为的评分也较DO天增高。与100g组和CCI组相反,400g组出现了明显的痛觉减退,表现为热痛阈和机械痛阈升高(P<0.05),尽管冷痛觉、动态触觉和疼痛相关行为的评分也一定程度的升高,但重触觉的变化却没有统计学意义(P>0.05)。
2.在背根节中,与Sham组相比,100g组和CCI组的IB4和CGRP阳性细胞数出现了短暂的减少,而400g的IB4和CGRP阳性细胞数出现了持久的、难以恢复的减少。在脊髓当中,与对侧相比,100g组、400g和CCI组腰膨大板层Ⅱ中的IB4纤维均出现了减少,但只有400g组的CGRP纤维出现了明显的减少(P<0.05),而100g组和CCI组的CGRP纤维面积没有出现变化。在坐骨神经中,波蒂安银染显示400g组第10天的神经纤维明显较另外两组和sham组稀疏。
结论
1.100g压力一过性挤压大鼠坐骨神经产生与CCI类似的神经病理性疼痛阳性症状；400g压力除了导致冷痛觉和动态触觉过敏外,大鼠同时出现以热痛觉和机械性痛觉减退为表现的阴性症状。
2.比较不同组之间DRG和脊髓中IB4和CGRP阳性细胞和神经纤维的动态变化进行分析,IB4神经细胞可能参与疼痛信号的中枢调控,而CGRP直接传递热痛等疼痛信号。
Objectives
Hypoalgesia denotes a decreased or increased threshold to thermal, cold or mechanical stimuli. Hypoalgesia occurs after nerve injury, diabetes mellitus or other central or peripheral neuropathies, which accompany with positive or negative sign of neuropathic pain. In our experiment, negative and positive signs are induced by crushing the rat scaitic nerve with different pressures measured by FSR sensor. Furthermore, DRG and spine immunofluerescence staining showed that transient loss of IB4positive non-peptidergic C fiber occurred in the CCI and light crush groups with signs of hyperalgesia, while longer loss of CGRP positive peptidergic C fiber occurred in the heavy crush group with signs of hypoalgesia. The different phenotype indicated that these two kinds of C fiber had distinct functions in the pain signaling pathways: thermal hypoalgesia after nerve injury was resulted by the loss of peptidergic C fiber; non peptidergic C fiber played an important role in the central modulation of pain signaling and the onset of positive signs. These data provided new insights into the comprehensive therapy of neuropathic pain.
Methods
1. Twenty four male SD rats were randomly divided into four group Sham (n=6),100g (n=6),400g(n=6)and group CCI (n=6). In group CCI, left sciatic nerve CCI model were established according to Bennett and Xie, in group Sham, left sciatic nerves were only exposed without ligation. In100g group and400g group, left sciatic nerves were crushed by100g and400g force respectively. Paw withdrawal threshold to mechanical stimuli(MWT) and paw withdrawal latency to a thermal nociceptive stimulus(TWL) were measured at1day before (baseline) and3,7,10,14,21,28days after operation in the lateral and medial part of both left and right paw. Evaluation of the cold allodynia, touch allodynia and pain-related behavior were performed at1day before (baseline) and3,7,10,14,21,28days after operation in both left and right paw. The animals were then sacrificed and the left sciatic nerve, L5DRG and lumbar enlargement of the spinal cord were harvested at7,10,21,28days after operation and immersed in4%formaldehyde for a night.
2. The harvested DRG and Spine were embedded with OCT and stained with double labeling immunofluorescence method. In DRG, the segments at200micron,250micron and300micron were chose to calculate positive cells. In Spine, the area of positive nerve sprouting in ipilateral and contralateral lamina2were calculated. The sciatic nerve were performed with bodian silver staining method and the fiber density were compared in four group.
Results
1. Compared to DO, both the100g group and CCI groups showed thermal and mechanical hyperalgesia (P<0.05), and the behavior test scores of dynamic allodynia, cold allodynia and pain-related behavior were higher than DO. On the contrary, the400g group showed obvious hypoalgesia, which presented as higher thresholds of thermal and mechanical pain (P<0.05). Although there were a slight increase of the behavior test scores on dynamic allodynia, cold allodynia and pain-related beavior, but without statistical significance.
2. In dorsal root ganglion (DRG), compared to the Sham group, the number of IB4and CGRP positive neurons showed temporary decrease in the100g group and CCI group, while presented as long lasting, unrestorable decrease in the400g group. In spinal cord, the decrease of IB4fibers in Lamina2of the lumbar enlargement comparing to the contra side was shown in all of the100g,400g and CCI groups, while the decrease of CGRP fibers was only detected in the400g group (P<0.05). In sciatic nerves, Bodian Silver Staining showed that the density of fibers on D3in the400g group was lower comparing with that in the other two groups.
Conclusions
1、100g crush generated a transient pressure on rat sciatic nerve, led to signs of hyperalgesia that similar to CCI model.400crush resulted to cold and touch allodynia, as well as negative signs presented as mechanical and heat hypoalgesia
2、Compare the dynamic changes of IB4and CGRP positive neurons and fibers in DRG and spinal cord between groups, IB4fibers may take part in the central regulatory mechanisms of pain signaling, while CGRP fibers directly transduct the thermal pain signal.
引文
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