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

在周围神经损伤后的病理性疼痛中，体感觉系统的神经元可塑性被认为直接参与其中。然而，有关分子和神经生物学机制的报道很少。本研究的目的是利用成熟的大鼠模型阐明病理性疼痛的分子机制，该模型可能引发胞内核加工的扰动，导致谷氨酸和sP的过度释放导致Ca2+的增加。此外，它还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。结扎大鼠左坐骨神经诱导神经性疼痛。麻醉下，将环形微透析导管与PE-10管一起植入鞘内，用于脊髓谷氨酸释放（HPLC）和药物注射。分别给予(1)n型Ca通道阻断剂（I.T.）， (2) 5-H…More T2A阻断剂（I.P.），或(3)4-甲基cathechol （4-MC， I.P.）。坐骨神经结扎后，大鼠表现为热痛觉过敏，脊髓谷氨酸释放增加，且随时间延长而增强。痛觉过敏初期，c-fos蛋白诱导脊髓神经元凋亡，中间神经元坏死。n型Ca通道阻滞剂和5-HT2A受体拮抗剂可显著减弱脊髓谷氨酸释放，同时降低脊髓间神经元凋亡和坏死的发生率。另外，4-MC通过诱导神经生长因子的合成，使脊髓谷氨酸释放减少，从而抑制了这些组织学变化。根据目前的研究，我们认为它在脑核过程中产生调节，这种调节源于脊髓谷氨酸神经系统的过度兴奋而导致细胞凋亡，并与神经性疼痛的表现有关。此外，对于慢性疼痛的转化，提示其与中间神经元功能障碍有关，促进了对神经免疫网络机制的进一步了解。除了外周5-HT2A阻滞剂和鞘内n型Ca通道阻滞剂的作用外，在临床情况下，神经生长因子的诱导恢复了细胞死亡的过程，证明了这些治疗在功能恢复中的应用。在未来，将需要研究移植和腺载体病毒NGF给药是否是神经性疼痛的重要治疗方法。少

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