Regenerations of Spinal Cord 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

• 批准号: 13470321
• 负责人: ISHIKAWA Toshizo
• 金额: $ 5.18万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470321/
• 关键词: NEUROPATHIC PAIN; NEURONAL PLASTICITY; SPINAL GLUTAMATE; C-FOS EXPRESSION; APOPTOSIS; CA ENTRY BLOCKER; NERVE GROWTH FACTOR; 痛み; 脊髄細胞; グルタメート神経

The neuronal plasticity of the spinal cord sensory system in pathological pain after peripheral nerve injury has recently recognized as pivotal mechanisms. However, there are no report concerning with combined mechanisms such as regeneration of cellular and functional derangements. The aim of the present study was to investigate 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 resulting from these mechanisms including suppression of afferent input and synthesis of nerve growth factor by magnetic field stimulation. In Rats, the neuropathic pain was produced by legation of left sciatic nerve. Under halothane anesthesia special designed micro dialysis catheter was intrathecally implanted along with PE-10 tube for the spinal glu … More tamate release (HPLC-UV) and drug injection, respectively. For the treatment (1) several kinds of N-type Ca channel blocker (IT), (2) magnetic field stimulation (MFS), or (3) MFS + anti NGF (4) MFS + 4-methyl catechol (4-MC, IP) was respectively administered. After 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). Both N-type Ca channel blocker and MFS significantly attenuated spinal glutamate release accompanied with decreased incidences of c-foes, apoptosis and necrosis of spinal cord neurons. In addition, pretreatment of anti NGF with MFS showed less sever of pain facilitation and 4-MC administration, which brings about the synthesis induction of the NGF that it attenuates the spinal glutamate release, and intracellular signaling including c-foes and that, suppresses these histological changes. Based on this study, it is suggested that possible involvement of 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. We also reconfirmed that generates modulation in the intracellular - nucleus process, which originates from the excessive excitation of the spinal cord glutamate nerve system and brings about the apoptosis. 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 these treatments to the functional recovery in the clinical situation that the induction of the nerve growth factor restores the process for cell death in addition to the usefulness of N-type Ca channel blocker and magnetic field stimulation. As future direction, it will be needed to establish the transplantation and adeno-vector virus NGF administration for possible treatment for neuropathic pain. Less

脊髓感觉系统的可塑性是周围神经损伤后病理性疼痛的重要机制。然而，目前还没有关于细胞再生和功能紊乱的联合机制的报道。本研究的目的是利用已建立的大鼠病理性疼痛模型研究脊髓神经元再生的可能性，该模型已知谷氨酸和sP的过度释放启动细胞核内加工的扰动，导致Ca 2+增加。我们研究了这些机制导致的治疗可能性，包括抑制传入输入和神经生长因子的合成通过磁场刺激。大鼠左侧坐骨神经切断后产生神经病理性疼痛。在氟烷麻醉下，将特制的微透析导管沿着PE-10管置入椎管内， ...更多信息 释放（HPLC-UV）和药物注射。分别给予N型钙通道阻滞剂（IT）、磁场刺激（MFS）、MFS +抗NGF（4）MFS + 4-甲基儿茶酚（4-MC，IP）治疗。神经损伤后5-10天内大鼠出现热痛敏，并伴有脊髓谷氨酸释放增加，且随时间延长而增强。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。N型钙通道阻滞剂和MFS均能显著抑制脊髓谷氨酸的释放，并减少脊髓神经元的c-foes、凋亡和坏死。另外，用MFS预处理抗NGF表现出较轻的疼痛易化和4-MC给药，这导致NGF的合成诱导，其减弱脊髓谷氨酸释放和细胞内信号传导，包括c-foes，并抑制这些组织学变化。根据这项研究，建议可能参与周围神经生长因子诱导的磁场刺激脊髓神经元的再生和相关的感觉系统，如病理性疼痛的衰减。我们还再次证实，脊髓谷氨酸神经系统的过度兴奋引起细胞内-核过程的调节，从而导致细胞凋亡。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。这证明了这些治疗在临床情况下对功能恢复的应用，即除了N型Ca通道阻滞剂和磁场刺激的有用性之外，神经生长因子的诱导恢复了细胞死亡的过程。作为未来的发展方向，将需要建立神经生长因子移植和腺病毒载体给药的可能治疗神经病理性疼痛。少

项目成果

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Nakanishi O., Ishikawa T., et al.: "Involvement of the spinal glutamate release in the inflammatoric and neuropathic pain in rat : modulation by N-type Ca channel blocker"Plasticity of Pain System. 1. 7-8 (2002)

Nakanishi O.、Ishikawa T. 等人：“大鼠炎症性疼痛和神经性疼痛中脊髓谷氨酸释放的参与：N 型 Ca 通道阻滞剂的调节”疼痛系统的可塑性。

Nakanishi O., Ishikawa T., et al: "Involvement of the spinal glutamate release in the inflammatoric and neuropathic pain in rat : modulation by N-type Ca channel blocker"Plasticity of Pain System. 1. 7-8 (2002)

Nakanishi O.、Ishikawa T. 等人：“大鼠炎症性疼痛和神经性疼痛中脊髓谷氨酸释放的参与：N 型 Ca 通道阻滞剂的调节”疼痛系统的可塑性。