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Regenerations of Spinal Neurons and its Sensory Function in Pathological Pain following Peripheral Nerve Injury

周围神经损伤后病理性疼痛中脊髓神经元的再生及其感觉功能

基本信息

批准号：
15390475
负责人：
ISHIKAWA Toshizo
金额：
$ 4.29万
依托单位：
YAMAGUCHI UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390475/
关键词：
NEUTROPATHIC PAIN NEURONAL PLASTICITY SPINAL GLUTAMATE C-FOS EXPRESSION APOPTOSIS Ca ENTRY BLOCKER NERVE GROWTH FACTOR

项目摘要

The neuronal regeneration of the peripheral-spinal cord sensory system in pathological pain after peripheral nerve injury has recently focused. However, there are no report concerning with either bone marrow stromal cell (BMSc) transplantation or trophic factor treatment for regeneration of cellular and functional derangements. We investigated the possibility of regeneration of spinal cord neurons of pathological pain using well-established rat model, which is known that the excessive release of glutamate and sP initiate perturbation of intracellular-nucleus processing resulting in increased Ca2+. In addition, we investigated possibilities for treatment by BMSc transplantation into spinal cord and synthesis of nerve growth factor by 4 methyl cathechol amine (4-MC).The rats were divided into following two studies, BMSc and 4-MC study, respectively. In BMSc study, rats were subjected to spinal cord injury by completion and touch-evoked allodynia combined with astrocyte growing after BMSc … More implantation (cultured neruspheas). In 4-MC study, the neuropathic pain was produced by legation of left sciatic nerve. The pain response (thermal hyperalgesia) combined with c-fos expression, apoptosis (TUNEL), and GFAP (astrocyte) at spinal cord were measured after nerve injury. For the treatment, (1) 4-MC, (2) magnetic field stimulation (MFS), (3) N-type Ca entry blocker, combined with anti-NGF, was respectively administered.After transplantation of intrathecal BMSc one fourth of rats can gait and pain sensation was improved. In these improved animals, astrocyte growing was evident at both ventral and dorsal horn of spinal cord. On the other hands, after sciatic nerve injury, rats showed thermal hyperalgesia accompanied with increased spinal glutamate release during 5-10 days and that was enhanced with time. There were c-foes protein expression and apoptosis of superficial layer of spinal cord during early state of the hyperalgesia followed by the necrosis of the laminate 3-4 (interneuron). In decreased pain sensation animals appeared astrocyte growing at around Rexed III where is selectively damaged neurons after nerve injury. 4-MC significantly improved neuropathic pain associated with decreased incidences of c-foes, apoptosis, necrosis, and GFAP immunoreactivity of spinal cord neurons. 4-MC administration, which brings about the synthesis induction of the Brain derivated trophic factor and NGF that it attenuates the spinal glutamate release, and intracellular signaling including c-foes and that, suppresses these histopathological changes.Based on present study, we demonstrated that possible improvement of pain sensation by peripheral nerve injury by injecting BMSc and trophic factor. In these functional recovery, the regeneration of neuron and astrocytes in Rexed III of spinal cord where is known as velnerable region and causes pain facilitation as disinhibitiom mechanisms. Otherwise, the peripheral nerve growth factors induced by magnetic field stimulation in regeneration of spinal cord neurons and related to attenuation of sensory systems such that of pathological pain. For the conversion to chronic pain, it was indicated that the dysfunction of the interneuron was concerned, and promotes further understand mechanisms of the nerve - immune network. It proves application of bone marrow stromal cells and trophic factor treatments to the functional recovery in the clinical situation As future direction, it will be needed to confirm safety of transplantation for possible treatment for neuropathic pain. Less

周围神经损伤后病理性疼痛中周围-脊髓感觉系统的神经元再生是近年来的研究热点。然而，目前还没有关于骨髓基质细胞（BMSc）移植或营养因子治疗再生的细胞和功能紊乱的报道。我们研究了病理性疼痛的脊髓神经元再生的可能性，使用成熟的大鼠模型，这是已知的谷氨酸和sP的过度释放启动细胞核内加工的扰动，导致Ca 2+增加。此外，我们还研究了BMSc脊髓内移植治疗和4-甲基乙酰胆碱胺（4-MC）合成神经生长因子的可能性。在BMSc研究中，大鼠通过完成和触摸诱发的异常性疼痛联合BMSc后星形胶质细胞的生长而遭受脊髓损伤 ...更多信息植入（培养的神经细胞）。在4-MC研究中，神经病理性疼痛由左侧坐骨神经结扎产生。观察神经损伤后痛反应（热痛敏）及脊髓c-fos表达、细胞凋亡（TUNEL）和胶质纤维酸性蛋白（GFAP）的变化。分别给予4-MC、磁场刺激（MFS）、N-型钙通道阻滞剂和抗神经生长因子（anti-NGF）治疗后，1/4的大鼠经鞘内移植BMSc后，步态和痛觉均得到改善。在这些改良的动物中，脊髓腹角和背角的星形胶质细胞生长明显。另一方面，大鼠坐骨神经损伤后，在5-10天内表现出热痛觉过敏，并伴有脊髓谷氨酸释放增加，且随时间推移而增强。痛敏早期脊髓浅层有c-foes蛋白表达和细胞凋亡，随后3-4层（中间神经元）坏死。在痛觉减退的动物中，出现了星形胶质细胞生长在Rexed III周围，这是神经损伤后选择性受损的神经元。4-MC显著改善神经病理性疼痛，并降低脊髓神经元的c-foes、凋亡、坏死和GFAP免疫反应性的发生率。4-MC给药，其引起脑衍生的营养因子和NGF的合成诱导，其减弱脊髓谷氨酸的释放，以及包括c-foes在内的细胞内信号传导，从而抑制这些组织病理学变化。在这些功能恢复中，脊髓Rexed III区神经元和星形胶质细胞的再生被称为可愈合区，并作为解除抑制机制引起疼痛易化。另外，磁场刺激诱导的周围神经生长因子参与脊髓神经元的再生，并与感觉系统的衰减，如病理性疼痛有关。对于向慢性疼痛的转化，提示中间神经元的功能障碍受到关注，促进了对神经免疫网络机制的进一步认识。这证明了骨髓基质细胞和营养因子治疗在临床情况下的功能恢复的应用。作为未来的方向，需要确认移植的安全性，以可能治疗神经病理性疼痛。少