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Spatio-temporal analysis by optical imaging of neural plasticity mechanism in neuropathic pain.

通过光学成像对神经病理性疼痛的神经可塑性机制进行时空分析。

基本信息

批准号：
15500270
负责人：
MATSUMURA Shinji
金额：
$ 2.37万
依托单位：
Kansai Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
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-15500270/
关键词：
Allodynia Spinal cord Neural plasticity Optical imagine Nitric oxide Intracellular calcium ion NMDA receptor Mouse nNOS受容体

项目摘要

Neuropathic pain arising from peripheral nerve injury often becomes intractable pain accompanied by tactile pain (allodynia) and hyperalgesia.After mice had become neuropathic pain induced by L5 spinal nerve transection, the increase in nitric oxide synthase (NOS) activity was observed in the superficial layer of dorsal horn in the spinal cord by NADPH diaphorase histochemistry. Using the nitric oxide (NO) detection dye, we confirmed that NO production increased in the spinal slice prepared from neuropathic mice and that the increase was more prominent in the ipsilateral side to the nerve transection than in the contralateral side. These increases in NOS activity and NO production in neuropathic mice were blocked by pretreatment of oral JTC-801, non peptidergic nociceptin antagonist. Although intraperitoneal injection of the nonselective NOS inhibitor significantly attenuated neuropathic hyperalgesia, inducible NOS-deficient mice showed neuropathic pain after L5 spinal nerve transectio … More n. These results suggest that nociceptin is involved in the maintenance of neuropathic pain and that the analgesic effect of JTC-801 on neuropathic pain is mediated by inhibition of NO production by neuronal NOS.Mice lacking the PACAP gene (PACAP^<-/->) did not exhibit neuropathic pain induced by nerve transection, whereas they did retain normal nociceptive responses. Intrathecal administration of NMDA induced mechanical allodynia in wild-type mice, but not in PACAP-/- mice. The NMDA-induced allodynia in PACAP-/- mice was reproduced by simultaneous intrathecal injection of PACAP with NMDA. Concomitant with the increase in PACAP immunoreactivity after nerve injury, NADPH-dependent NOS activity markedly increased in the superficial layer of the spinal cord of wild-type mice. Simultaneous addition of PACAP and NMDA caused translocation of neuronal NOS from the cytosol to the membrane and stimulated NO production in vitro. These results demonstrate that PACAP might promote the functional coupling of neuronal NOS to NMDA receptors for neuropathic pain to occur. Less

由周围神经损伤引起的神经性疼痛常变为顽固性疼痛，并伴有触觉痛和痛觉过敏。L5脊髓神经横断致小鼠神经性疼痛后，通过NADPH脱氢酶组织化学观察到脊髓背角浅层一氧化氮合酶（NOS）活性升高。利用一氧化氮（NO）检测染料，我们证实了神经病变小鼠脊髓切片中NO的产生增加，并且神经横断的同侧比对侧增加更明显。神经病变小鼠NOS活性和NO生成的增加可通过口服非多肽性痛觉肽拮抗剂JTC-801预处理而被阻断。虽然腹腔注射非选择性NOS抑制剂能显著减轻神经性痛觉过敏，这些结果表明，痛觉肽参与了神经性疼痛的维持，而JTC-801对神经性疼痛的镇痛作用是通过抑制神经元NO的产生而介导的。缺乏PACAP基因（PACAP^<-/->）的小鼠不表现出神经横断引起的神经性疼痛，而保持了正常的伤害性反应。鞘内给药NMDA可诱导野生型小鼠机械性异常痛，而PACAP-/-小鼠无此作用。同时鞘内注射NMDA诱导的PACAP-/-小鼠异位性疼痛。神经损伤后，在PACAP免疫反应性升高的同时，野生型小鼠脊髓浅层nadph依赖性NOS活性显著升高。同时添加PACAP和NMDA可使神经元NOS从胞浆转移到膜上，并刺激体外NO的产生。这些结果表明，PACAP可能促进神经元NOS与NMDA受体的功能偶联，从而导致神经性疼痛的发生。少