臂丛损伤后脊神经和脊髓中炎性细胞浸润、ERK通路激活和c-Fos表达的实验研究
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摘要
臂丛神经损伤会引起神经病理痛特别是灼性痛,给患者造成极大的痛苦,现在还无有效的治疗方法。虽然臂丛损伤后,神经断裂造成所支配肌肉的运动障碍和皮肤的感觉功能消失,但一个难以忍受的疼痛患肢,比一个无功能患肢更使病人痛苦,更使临床医师棘手。虽然,对周围神经损伤诱发的神经痛机制的实验研究很多,但几乎都集中于腰、骶部神经,且多用的是脊神经神经干损伤或外周支配皮区的化学性损伤模型,而直接研究臂丛损伤后神经病理痛发生机制的研究罕见。臂丛损伤有其特殊性,特别是臂丛根性撕脱伤不仅有神经传入、传出信息的中断,而且由于神经根的撕脱造成与其相连的脊髓部位的损伤、炎症及渗透压、组织压、组织代谢的破坏,也可能直接影响上位脑结构的下行感觉调控通路的完整性,干扰机体内神经-体液抗痛系统的功能,因此,臂丛神经根性撕脱伤的特殊性在于不仅有周围神经包括交感纤维的损伤,同时还有中枢结构的损伤,复杂因素的叠加可能与顽固性的灼性神经痛的发生有关。但哪一条途径是主要因素,为什么单纯的中枢神经损伤或单纯的周围神经损伤,就没有如此高的发病率,是否存在某一个激发因素是臂丛灼性神经痛发生的关键环节,目前还没有针对性的研究,因而也缺乏有效的治疗方法,给临床选择缓解疼痛的治疗方法带来困难。对此问题进行研究具有重要理论意义和应用价值。
臂丛撕脱伤是最近刚建立的一个神经病理痛模型。这种损伤引起了中枢系统中疼痛感觉相关区域的病理可塑性变化。臂丛撕脱伤神经病理痛的典型特点是术后的急性疼痛(臂丛损伤后立即出现)和持续时间很长的慢性神经病理痛,这种慢性神经病理痛甚至会蔓延到离损伤很远的区域,包括损伤的同侧和对侧。
诸多研究表明:除神经元和和胶质细胞的结构和功能改变外,炎性细胞和炎性因子在神经病理痛的发展阶段也发挥了重要作用。本研究针对这个问题,首先建立了臂丛撕脱伤的动物模型,然后在这个模型下研究了脊神经根、背根神经节和脊髓中炎性细胞的浸润、ERK通路的激活和,即早基因c-Fos的表达和后脚痛阈变化时程上的关系。初步探讨了这些分子在臂丛撕脱伤引起后脚痛阈变化中的作用.
主要结果:
1.成功建立了臂丛下干离断和根性撕脱的动物模型,用von Frey方法测定后脚痛阈变化,结果显示:臂丛下干离断和根性撕脱伤都能引起大鼠后脚机械性痛觉增敏,但臂丛下干根性撕脱伤引起的机械性痛敏增高的时间更短,反应更强烈。两种损伤方式的差异显著。
2.正常情况下,磷酸化ERK(P-ERK)样免疫反应(-LI)在周围神经的雪旺氏细胞中围绕郎飞氏节呈节段样分布,下干剪断后5h这种分布消失,一直到24h时节状分布才重新出现,3d后节段样分布完全恢复,这种变化可能是损伤造成的急性反应性变化。
3.臂丛下干切断伤和撕断伤都可以引起下干中中性粒细胞、淋巴细胞的浸润,雪旺氏细胞中ERK通路的激活和c-Fos的强烈表达。离断后主要集中在断口处,而撕脱伤范围更广,脊神经、背根节和中枢支都有,且背根节中卫星细胞和部分神经元中ERK通路被激活。
4.臂丛下干根性撕脱伤后相应节段脊髓背角固有核、后角连合核以及脊髓灰质背角胶状质中的细胞被强烈激活,磷酸化ERK1/2表达增加,3d达到高峰。另外,损伤侧楔束中的细胞也出现P-ERK-LI,持续达30d。
结论:
本实验结果表明,臂丛撕脱伤引起残留的神经、背根节和脊髓中炎性细胞的浸润和部分神经元、雪旺氏细胞、脊髓中胶质细胞的活化,且脊髓背索胶质细胞和脊髓灰质背角ERK通路也被激活。这些因素可能和灼性痛的产生机制有关。
In clinic, a few patients suffer serious neurophathic pain caused by brachial plexus injury, on which there is still no effective treatment to relieve the pain yet. Although the injury causes sensation and movement disability, the neuropathic pain is the most conspicuous symptom the patient can not tolerate. Although researchers had put a lot of effort on study of the mechanism of neuropathic pain, most of the animal models are focused on the nerve of hind limb to attempt to mimic the observed clinical consequences of nerve injury. Although most of these models have been useful in the experimental analysis of the pathological processes in the nerve itself, few of them reproduce changes in pain sensation like those that accompany peripheral neuropathies in humans. Therefore, new and reliable models of neuropathic persistent pain are still needed. Brachial plexus injury, caused by spinal cord root avulsion and particularity, produces a characteristic constant crushing and intermittent shooting pain that is often intractable. This lesion may lead to important pathological changes responsible for increased pain sensations. The main characteristics of brachial plexus injury are the rapid onset of pain, which occurs immediately after the trauma, and the development of a trigger point, which may be distant to the site of the lesion, either on the ipsilateral or contralateral side.The brachial plexus avulsion (BPA) has been recently described for rats as a new model of long-lasting neuropathic pain. This lesion may lead to pathological plasticity of the central nervous system that is associated with altered pain sensations (Carvalho et al., 1997). The main characteristics of BPA are the rapid onset of pain (an effect which occurs immediately after the trauma) and the long-lasting development of neuropathy, which may be evidenced distant from the site of the lesion, either on the ipsilateral or contralateralside.
It has been proved immune and inflammatory mechanisms play important role in the development of neuropathic pain, during the development MAPK signal pathway and C-Fos is often take part in.
In the present study, we aimed at reproducing a rat model previously described by Rodrigues-Filho et al. (2003), giving special attention to the definition of the activity of neutrophages infiltration, the activity of ERK and the C-Fos expression in the development of neuropathic pain.
Main result:
1. Rat model of brachial plexus injury was successfully reproduced. Von Frey fligament were used to identity the development of mechanical allodynia. The result proved that the significant mechanical hyperalgesia was formed in the experimental animals.
2. ERK-LI that constantly expressed in Schwann cells was down-regulated transiently 5h after the low branch of brachial plexus were cut. Twenty-four hors after cutting, the ERK-LI is slowly up-regulated, and 3d latter it has recovered to the level as control.
3. Lower branch of the brachial plexus avulsion caused more serious neutrophages infiltration, ERK1/2 signal pathway was strongly activated along the lower trunk, c-Fos was strongly up-regulated in the same trunk.
4. Lower branch of the brachial plexus avulsion activated ERK pathways in the dorsal horn of gray matter. In addition, ERK pathways of the glia cell in fasciculus cuneatus was also strongly activated and lasted at least thirty days after avulsion.
Conclusion:
In this study, we proved that brachial plexus avulsion causes serious neutrophages infiltration in the lower trunk, ERK pathway was strongly activated and C-Fos expression was strongly upregulated in the lower trunk. In the spinal cord, ERK 1/2 in the gray matter and in the glia cell of fasciculus cuneatus is strongly activated. These changes might be related to the production and maintenance of neuropathic pain following bronchial plexus avulsion.
臂丛撕脱伤是最近刚建立的一个神经病理痛模型。这种损伤引起了中枢系统中疼痛感觉相关区域的病理可塑性变化。臂丛撕脱伤神经病理痛的典型特点是术后的急性疼痛(臂丛损伤后立即出现)和持续时间很长的慢性神经病理痛,这种慢性神经病理痛甚至会蔓延到离损伤很远的区域,包括损伤的同侧和对侧。
诸多研究表明:除神经元和和胶质细胞的结构和功能改变外,炎性细胞和炎性因子在神经病理痛的发展阶段也发挥了重要作用。本研究针对这个问题,首先建立了臂丛撕脱伤的动物模型,然后在这个模型下研究了脊神经根、背根神经节和脊髓中炎性细胞的浸润、ERK通路的激活和,即早基因c-Fos的表达和后脚痛阈变化时程上的关系。初步探讨了这些分子在臂丛撕脱伤引起后脚痛阈变化中的作用.
主要结果:
1.成功建立了臂丛下干离断和根性撕脱的动物模型,用von Frey方法测定后脚痛阈变化,结果显示:臂丛下干离断和根性撕脱伤都能引起大鼠后脚机械性痛觉增敏,但臂丛下干根性撕脱伤引起的机械性痛敏增高的时间更短,反应更强烈。两种损伤方式的差异显著。
2.正常情况下,磷酸化ERK(P-ERK)样免疫反应(-LI)在周围神经的雪旺氏细胞中围绕郎飞氏节呈节段样分布,下干剪断后5h这种分布消失,一直到24h时节状分布才重新出现,3d后节段样分布完全恢复,这种变化可能是损伤造成的急性反应性变化。
3.臂丛下干切断伤和撕断伤都可以引起下干中中性粒细胞、淋巴细胞的浸润,雪旺氏细胞中ERK通路的激活和c-Fos的强烈表达。离断后主要集中在断口处,而撕脱伤范围更广,脊神经、背根节和中枢支都有,且背根节中卫星细胞和部分神经元中ERK通路被激活。
4.臂丛下干根性撕脱伤后相应节段脊髓背角固有核、后角连合核以及脊髓灰质背角胶状质中的细胞被强烈激活,磷酸化ERK1/2表达增加,3d达到高峰。另外,损伤侧楔束中的细胞也出现P-ERK-LI,持续达30d。
结论:
本实验结果表明,臂丛撕脱伤引起残留的神经、背根节和脊髓中炎性细胞的浸润和部分神经元、雪旺氏细胞、脊髓中胶质细胞的活化,且脊髓背索胶质细胞和脊髓灰质背角ERK通路也被激活。这些因素可能和灼性痛的产生机制有关。
In clinic, a few patients suffer serious neurophathic pain caused by brachial plexus injury, on which there is still no effective treatment to relieve the pain yet. Although the injury causes sensation and movement disability, the neuropathic pain is the most conspicuous symptom the patient can not tolerate. Although researchers had put a lot of effort on study of the mechanism of neuropathic pain, most of the animal models are focused on the nerve of hind limb to attempt to mimic the observed clinical consequences of nerve injury. Although most of these models have been useful in the experimental analysis of the pathological processes in the nerve itself, few of them reproduce changes in pain sensation like those that accompany peripheral neuropathies in humans. Therefore, new and reliable models of neuropathic persistent pain are still needed. Brachial plexus injury, caused by spinal cord root avulsion and particularity, produces a characteristic constant crushing and intermittent shooting pain that is often intractable. This lesion may lead to important pathological changes responsible for increased pain sensations. The main characteristics of brachial plexus injury are the rapid onset of pain, which occurs immediately after the trauma, and the development of a trigger point, which may be distant to the site of the lesion, either on the ipsilateral or contralateral side.The brachial plexus avulsion (BPA) has been recently described for rats as a new model of long-lasting neuropathic pain. This lesion may lead to pathological plasticity of the central nervous system that is associated with altered pain sensations (Carvalho et al., 1997). The main characteristics of BPA are the rapid onset of pain (an effect which occurs immediately after the trauma) and the long-lasting development of neuropathy, which may be evidenced distant from the site of the lesion, either on the ipsilateral or contralateralside.
It has been proved immune and inflammatory mechanisms play important role in the development of neuropathic pain, during the development MAPK signal pathway and C-Fos is often take part in.
In the present study, we aimed at reproducing a rat model previously described by Rodrigues-Filho et al. (2003), giving special attention to the definition of the activity of neutrophages infiltration, the activity of ERK and the C-Fos expression in the development of neuropathic pain.
Main result:
1. Rat model of brachial plexus injury was successfully reproduced. Von Frey fligament were used to identity the development of mechanical allodynia. The result proved that the significant mechanical hyperalgesia was formed in the experimental animals.
2. ERK-LI that constantly expressed in Schwann cells was down-regulated transiently 5h after the low branch of brachial plexus were cut. Twenty-four hors after cutting, the ERK-LI is slowly up-regulated, and 3d latter it has recovered to the level as control.
3. Lower branch of the brachial plexus avulsion caused more serious neutrophages infiltration, ERK1/2 signal pathway was strongly activated along the lower trunk, c-Fos was strongly up-regulated in the same trunk.
4. Lower branch of the brachial plexus avulsion activated ERK pathways in the dorsal horn of gray matter. In addition, ERK pathways of the glia cell in fasciculus cuneatus was also strongly activated and lasted at least thirty days after avulsion.
Conclusion:
In this study, we proved that brachial plexus avulsion causes serious neutrophages infiltration in the lower trunk, ERK pathway was strongly activated and C-Fos expression was strongly upregulated in the lower trunk. In the spinal cord, ERK 1/2 in the gray matter and in the glia cell of fasciculus cuneatus is strongly activated. These changes might be related to the production and maintenance of neuropathic pain following bronchial plexus avulsion.
引文
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