Elucidation of Molecular and Neurobiological Mechanism in Pathophysiological Pain following Peripheral Injury

外周损伤后病理生理疼痛的分子和神经生物学机制的阐明

• 批准号: 10470318
• 负责人: ISHIKAWA Toshizo
• 金额: $ 5.95万
• 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: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470318/
• 关键词: Neuropathic Pain; Neuronal Prasticity; Spinal glutamate; C-fos Expression; Apoptosis; Necrosis of Interneurons; Treatment of Nerve Growth Factor; 神経因性疼痛; 神経可塑性; 脊髄グルタメート; c-fos発現; アポトーシス; 介在ニューロン死; Neuropathic pain; Central sensitization; S

In pathological pain after peripheral nerve injury, the neuronal plasticity of the somatosensory system is recently thought to be directly involved. However, there are few report concerning with molecular and neurobiological mechanisms. The aimof the present study was to elucidate the molecular mechanism of pathological pain using well-established rat model, which may initiate perturbation of intracellular-nucleus processing resulting in increased Ca2+ caused by excessive release of glutamate and sP. In addition, it was to investigate possibilities for treatment resulting from these mechanisms including suppression of afferent input and synthesis of nerve growth factor.Using rats the left sciatic nerve was ligated to induce the neuropathic pain. Under anesthesia loop-type microdialysis catheter was intrathecally implanted along with PE-10 tube for the spinal glutamate release (HPLC) and drug injection, respactively. For the treatment either (1) N-type Ca channel blocker (I.T.), (2) 5-H … More T2A blocker (I.P.), or (3) 4-methyl cathechol (4-MC, I.P.) was respectively administered.After sciatic nerve ligation, rats showed thermal hyperalgesia accompanied with increased spinal glutamate release and that was enhanced with time. There were c-fos protein induction and apoptosis of spinal cord neurons in the initial state of the hyperalgesia followed by the necrosis of the interneurons. N-type Ca channel blocker and 5-HT2A receptor antagonist significantly attenuates spinal glutamate release accompanied with decreased incidences of apoptosis and necrosis of interneurons at spinal cord. In addition, 4-MC administration, which brings about the synthesis induction of the nerve growth factor that it, attenuates the spinal glutamate release and that suppresses these histological changes.Based on the present study, it is suggested that it generates modulation in the intrellular-nucleus process, which originates from the excessive excitation of the spinal cord glutamate nerve system and brings about the apoptosis, and that this is concerned in the manifestation in neuripathic pain. In addition, for the con version to chronic pain, it was indicated that the dysfunction of the interneuron was concerned, and promotes further understand mechanisms of the nerve - immuno network. In 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 peripheral 5-HT2A blocker and intrathecal N-type Ca channel blocker. In the future, it will be needed to examine whether transplantation and adeno-vector virus NGF administration are significant treatment for neuropathic pain. Less

在周围神经损伤后的病理性疼痛中，躯体感觉系统的神经元可塑性最近被认为直接参与。然而，关于其分子和神经生物学机制的报道很少。本研究的目的是使用成熟的大鼠模型阐明病理性疼痛的分子机制，该模型可能启动细胞核内加工的扰动，导致谷氨酸和sP的过度释放引起的Ca 2+增加。本研究旨在研究由这些机制引起的治疗的可能性，包括抑制传入输入和神经生长因子的合成。结扎坐骨神经以诱导神经病理性疼痛。麻醉下鞘内沿着PE-10管置入环型微透析导管，分别用于脊髓谷氨酸释放（HPLC）和药物注射。对于治疗，（1）N-型Ca通道阻断剂（I.T.），(2)5-H ...更多信息 T2 A阻滞剂（腹腔注射），或（3）4-甲基儿茶酚（4-MC，I. P.）坐骨神经结扎后，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。在痛敏的初始阶段，脊髓神经元出现c-fos蛋白诱导和凋亡，随后出现中间神经元坏死。N型钙通道阻滞剂和5-HT 2A受体拮抗剂可明显抑制脊髓谷氨酸的释放，并减少脊髓中间神经元的凋亡和坏死。此外，4-MC的作用是诱导神经生长因子的合成，从而抑制脊髓谷氨酸的释放，抑制这些组织学变化，因此，本研究认为，4-MC对脊髓谷氨酸神经系统的过度兴奋引起的内核突产生调制，导致细胞凋亡，并且这与神经性疼痛的表现有关。另外，对于慢性疼痛的转化，提示了中间神经元的功能障碍，促进了对神经免疫网络机制的进一步认识。证明了这些治疗在临床情况下对功能恢复的应用，即除了外周5-HT 2A阻断剂和鞘内N型Ca通道阻断剂的有用性之外，神经生长因子的诱导恢复了细胞死亡的过程。在未来，这将需要检查是否移植和腺病毒载体神经生长因子管理是重要的治疗神经性疼痛。少

项目成果

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Ishikawa T.：“脊髓甘氨酸或GABAA受体拮抗剂产生的脊髓氨基酸释放和触摸引起的异常性疼痛的特征”神经科学95・3（2000）。

ISHIKAWA, T. et al: "Synergic drug effects on tactile allodynia by GABAA receptor antagonist"Soc. for Neurosci. 25. 934 (1999)

ISHIKAWA, T. 等人：“GABAA 受体拮抗剂对触觉异常性疼痛的协同药物作用”Soc。

ISHIKAWA, T. et al: "Modulation of formalin-evoked hyperalgesia by intrathecal N-type Ca channel and protein Kinase C inhibitor in the rat"Cell Moll Neurobiol. 19(2). 191-197 (1999)

ISHIKAWA, T. 等人：“在大鼠中通过鞘内 N 型 Ca 通道和蛋白激酶 C 抑制剂调节福尔马林诱发的痛觉过敏”Cell Moll Neurobiol。

Ishikawa T.et al.: "Synetgic durg effects on tactile allodynja by GABAA receptor antagonist"Soc.for Neurosci. 25. 934 (1999)

Ishikawa T.等人：“GABAA 受体拮抗剂对触觉异常疼痛的协同药物效应”Soc.for Neurosci。

Ishikawa T.: "Synergic drug effects on tactile allodynia by GABAA receptor antagonist"Soc. For Neuroscience. 25. 934 (1999)

Ishikawa T.：“GABAA 受体拮抗剂对触觉异常性疼痛的协同药物作用”Soc。