SNAP25调控神经病理性疼痛的分子机制研究

项目名称： SNAP25调控神经病理性疼痛的分子机制研究

项目编号： No.81471135

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 邹望远

作者单位： 中南大学

项目金额： 70万元

中文摘要： 神经病理性疼痛的机制尚不完全清楚，我们通过蛋白质组学研究发现神经病理性疼痛大鼠脊髓组织的突触相关蛋白SNAP25表达上调，下调PKC表达可逆转SNAP25表达上调，鞘内注射可特异性水解SNAP25蛋白的肉毒素A（BoNT/A）对病理性疼痛大鼠有镇痛作用。因此我们提出假说：外周神经损伤引起的伤害性信息通过背根神经节传入至脊髓背角，激活PKC，磷酸化SNAP25，SNAP25 进一步通过突触前机制增加脊髓背角兴奋性神经递质（如谷氨酸）的释放，或/和通过调控兴奋性/抑制性神经递质转运体（如谷氨酸转运体、甘氨酸转运体及GABA转运体）减少兴奋性递质的转运及增加抑制性递质的转运，导致兴奋/抑制性神经递质失衡，神经递质作用于突触后膜的NMDA/AMPA、Gly及GABA等受体，从而介导神经病理性疼痛的发生发展。本项目为阐明SNAP25调控兴奋/抑制性神经递质参与神经病理性疼痛的分子机制提供实验依据。

中文关键词： 神经病理性疼痛；突触相关蛋白25；神经递质；谷氨酸转运体；甘氨酸转运体

英文摘要： Neuropathic pain results from a lesion or disease affecting the somatosensory system at either the peripheral or central level.And the mechanisms of neuropathic pain are pooly understood. Our previous study of proteomics at the spinal cord level,for the first time,discovered that SNAP25(synaptosomal-associated protein,25kDa )was downregulated with CCI-induced neuropathic pain rats,and can be reversed by PKC knockdown in the spinal cord.Then we further intrathecal injection of BoNT/A, the reduction of SNAP-25 was correlated with the relief of mechanical allodynia and thermal hyperalgesia induced by CCI-induced neuropathic pain rats.So we hypothesized that SNAP-25 may involed in the development and maintenance of neuropathic pain. SNAP-25 was phosphorylated and up-regulated in the spinal cord dorsal horn by peripheral nerve injury, which in turn increase the release of excitatory neurotransmitters (such as glutamate) from spinal cord neuron through pre-synaptic mechanism,or/and increase the transportation of excitatory neurotransmitter by glutamate neurotransmitter transporters(such as GLT-1 and VGLUTs), and reduces the transportation of inhibitory neurotransmitters（such as glycine and GABA） through regulating the functions of inhibitory neurotransmitter transporters(such as GlyT1,GlyT2,GAT-1 and VGAT)，then the neurotransmitters act on NMDA/AMPA,Gly and GABA receptors, and results in imbalance between the excitatory and inhibitory neurotransmitters.Our proposed study will unveil the mechanisms of SNAP-25 involvement in the development and maintenance of neuropathic pain, and provide experimental basis for the molecular machanisms of neuropathic pain.

英文关键词： Neuropathic pain;SNAP25;Neurotransmitter;Glutamate transporter;Glycine transporter