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

神经性疼痛通常是由组织损伤或手术后周围神经损伤、脊髓损伤、糖尿病周围神经病变、疱疹后神经病变引起的。在这种病理状态下，即使轻微触摸皮肤也会产生转导性疼痛，即触觉异常性疼痛。产生异位性疼痛的机制尚不清楚，治疗神经性疼痛的药物也还没有找到。鞘内注射血小板活化因子（PAF）通过激活PAF受体和随后的ATP-P2X和NMDA受体以及随后的NO合成途径诱导强效异常性痛。鞘内注射cGMP类似物，8-pCPT-cGMP在小鼠中产生强烈的触觉异常性痛。7-硝基吲唑可阻断PAF和谷氨酸诱导的异位痛，而SIN-1和8-pCPT-cGMP诱导的异位痛不被7-硝基吲唑阻断。鞘内注射可溶性g -环化酶抑制剂（如ODQ和NS 2028）可防止PAF、谷氨酸和sin1诱导的异位性疼痛，而不是8-pCPT-cGMP。鞘内预处理Rp-8-pCPT-cGMPS （ccmp依赖性蛋白激酶（PKG）抑制剂）可阻断PAF、谷氨酸、SIN-1和8-pCPT-cGMP对异位性痛的诱导。吗啡、QYNAD和米诺环素阻断paf诱导的异常性疼痛。PAF刺激DRG的ATP释放和OX-42阳性小胶质细胞在背角的积累。白细胞介素-1降低P/Q型Ca^<2+>通道的表达。一些非甾体抗炎药通过阻断MRPs抑制神经毒素的反向转运并增强其细胞毒性。鞘内注射氨氮平（甘氨酸转运蛋白抑制剂）可减少8-pCPT-cGMP诱导的异位性疼痛。这些结果表明，刺激ATP和谷氨酸的释放、NO的产生以及随之而来的可溶性g -环化酶和PKG的激活在PAF和谷氨酸的有害信号转导中发挥了关键作用。小胶质细胞可能参与了这一过程。甘氨酸转运蛋白抑制剂通过增强甘氨酸能在脊髓中的抑制神经传递，产生了有效的抗异动作用，可能成为神经性疼痛治疗的新候选药物。本研究结果表明，paf诱导的异位性疼痛可能是研究异位性疼痛机制和开发新型抗异位性药物的良好模型。少

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