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

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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