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The role of Platelet-Activating Factor (PAF) on the mechanisms of development of neuropathic pain. And its regulation

血小板激活因子（PAF）在神经性疼痛发生机制中的作用。

基本信息

批准号：
15390562
负责人：
DOHI Toshihiro
金额：
$ 9.47万
依托单位：
HIROSHIMA 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 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390562/
关键词：
Platelet-Activating Factor Neuropathic pain Allodynia cGMP ATP NO Microglia Glvcine transporter 血書版活性化因子 PAF 脊髄慢性疼痛神経損傷

项目摘要

Neuropathic pain which is often produced by peripheral nerve injury after tissue damage or surgery, injury of spinal cord, diabetic peripheral neuropathy, post-herpetic neuropathy. In such pathological conditions, even light touch to skin become to transduce pain, tactile allodynia. The mechanisms for production of allodynia are far from understanding, and medicaments for treatment of neuropathic pain are not available.Platelet-activating factor (PAF) injected intrathecally induced potent allodynia by the pathway of the activation of PAF receptors and subsequent ATP-P2X and NMDA receptors and subsequent NO synthesis. Intrathecal injection of an analog of cGMP,8-pCPT-cGMP produced potent tactile allodynia in mice. Allodynia induced by PAF and glutamate was blocked by 7-nitroindazole while allodynia induced by SIN-1 and 8-pCPT-cGMP was not blocked by 7-nitroindazole. Intrathecal injections of soluble G-cyclase inhibitors such as ODQ and NS 2028 protected from the induction of allodynia b … More y PAF, glutamate and SIN-1 but not 8-pCPT-cGMP. Pretreatment with intrathecal Rp-8-pCPT-cGMPS, an inhibitor of cGMP-dependent protein kinase (PKG), blocked the induction of allodynia by PAF, glutamate, SIN-1 and 8-pCPT-cGMP. PAF-induced allodynia was blocked by morphine, QYNAD and minocycline. PAF stimulated ATP release from DRG and the accumulation of OX-42 positive microglia in dorsal horn. Interleukin-1 reduced the expression of P/Q type Ca^<2+> channel. Some NSAIDs inhibited the reverse transport of neurotoxin by blocking MRPs and potentiated its cytotoxicity. Intrathecal injection of amozapin, an inhibitor of glycine transporter reduced allodynia induced by 8-pCPT-cGMP. These results suggest that stimulation of ATP and glutamate release, the production of NO and the following activation of soluble G-cyclase and PKG play key roles for the transduction of the noxious signaling for PAF and glutamate in spinal cord. Microglia may be involved in this process. Glycine transporter inhibitors by enforcing glycinergic inhibitory neurotransmission in spinal cord produced potent anti-allodynic effect and may be novel candidate for medicament of neuropathic pain.The present results suggest that PAF-induced allodynia may be a good model for research of the mechanisms of allodynia and development of novel ant-allodynic medicaments. Less

神经病理性疼痛常由组织损伤或手术后的周围神经损伤、脊髓损伤、糖尿病周围神经病变、疱疹后神经病变等引起。在这种病理条件下，即使轻轻触摸皮肤也会导致疼痛、触觉异常性疼痛。鞘内注射血小板活化因子（PAF）可通过激活PAF受体，继而激活ATP-P2 X和NMDA受体，进而诱导NO的合成，从而诱导痛觉超敏。鞘内注射cGMP类似物8-pCPT-cGMP在小鼠中产生有效的触觉异常性疼痛。7-硝基吲唑可阻断PAF和谷氨酸诱发的痛觉超敏反应，而不能阻断SIN-1和8-pCPT-cGMP诱发的痛觉超敏反应。鞘内注射可溶性G-环化酶抑制剂如ODQ和NS 2028可防止诱发异常性疼痛B ...更多信息 y PAF、谷氨酸和SIN-1，但不含8-pCPT-cGMP。鞘内注射cGMP依赖性蛋白激酶（PKG）抑制剂Rp-8-pCPT-cGMPS可阻断PAF、谷氨酸、SIN-1和8-pCPT-cGMP对痛觉超敏的诱导作用。PAF诱发的痛觉超敏反应可被吗啡、QYNAD和米诺环素阻断。PAF刺激背根节ATP的释放和OX-42阳性小胶质细胞在背角的聚集。白细胞介素-1降低P/Q型Ca^2+通道的表达。部分非甾体类抗炎药通过阻断MRPs抑制神经毒素的逆向转运，增强其细胞毒性。鞘内注射甘氨酸转运体抑制剂amozapin可减少8-pCPT-cGMP诱导的异常性疼痛。这些结果提示，刺激脊髓内ATP和谷氨酸的释放、NO的产生以及随后可溶性G环化酶和PKG的激活在PAF和谷氨酸伤害性信号转导中起关键作用。小胶质细胞可能参与了这一过程。甘氨酸转运体抑制剂通过增强脊髓甘氨酸能抑制性神经传递而产生抗异常性疼痛的作用，有望成为神经病理性疼痛治疗的新候选药物，本研究结果提示PAF诱导的异常性疼痛可能是研究异常性疼痛机制和开发新型抗异常性疼痛药物的良好模型。少