Microglia, Complement, and Pain

描述（由申请人提供）：外周神经性疼痛由外周和中枢神经系统的多种变化引起，包括免疫系统和神经系统之间的相互作用。我们从微阵列表达谱分析中发现，背角小胶质细胞的免疫基因激活是啮齿动物周围神经性疼痛模型的一个主要共同特征，其中最显著的是脊髓补体级联成分的局部诱导。此外，通过消耗大鼠脊髓或突变小鼠中的补体级联成分来阻断补体级联，可以减少神经性疼痛模型中的疼痛超敏反应。基于此，我们假设周围神经损伤导致受伤的感觉神经元产生信号，该信号被运送到三叉神经背角/脊髓核传入神经的中央末端，在那里它作用于小胶质细胞诱导补体基因。经典补体级联通路在背浅角的局部激活导致C5a过敏毒素的产生和膜攻击复合物（MAC）的组装。我们推测，C5a通过C5a受体改变小胶质细胞和神经元的功能，而MAC则专门组装在那些不表达CD59的神经元上，CD59是MAC组装的内源性抑制剂，通过增加神经元中的钙流入，增加它们的兴奋性和细胞凋亡的易感性。为了验证这一假设，我们建议确定：1)哪些外围刺激；2)哪些细胞因子和趋化因子诱导了小胶质细胞中的补体基因；3)补体级联在神经性疼痛产生中的作用，特别是C5a或MAC的组装是否是疼痛的主要效应因子；4)补体激活是否足以改变背角神经元的兴奋性，从而产生兴奋性毒性凋亡。我们将利用这些信息设计和测试基于阻断小胶质细胞补体基因诱导或神经系统补体级联激活的躯体和面部神经性疼痛的新治疗策略。

DESCRIPTION (provided by applicant): Peripheral neuropathic pain arises from diverse changes in the peripheral and central nervous systems that include a reciprocal interaction between the immune and nervous systems. We find from a microarray expression profile analysis that immunologic gene activation in microglia in the dorsal horn is a major common feature of rodent peripheral neuropathic pain models and includes most prominently a local induction of components of the complement cascade in the spinal cord. Blocking the complement cascade by depleting its components in rat spinal cord or in mutant mice reduces, moreover, pain hypersensitivity in neuropathic pain models. Based on this, we hypothesize that peripheral nerve injury results in production by injured sensory neurons of a signal that is transported to the central terminals of the afferents in the dorsal horn/spinal nucleus of the trigeminal where it acts on microglia to induce complement genes. Activation of the classical complement cascade pathway locally in the superficial dorsal horn results in production of C5a anaphylatoxin and assembly of the membrane attack complex (MAC). C5a, we hypothesize, acts via the C5a receptor to alter microglial and neuronal function, while MAC, we propose, is specifically assembled on those neurons that do not express CD59, an endogenous inhibitor of MAC assembly, and by increasing calcium influx in the neurons, increases their excitability and vulnerability to apoptosis. To test this hypothesis we propose to determine: 1) Which peripheral stimuli; activity, inflammation or axonal damage, induce complement genes in microglia in the dorsal horn 2) Which cytokines and chemokines induce complement genes in microglia, 3) The role of the complement cascade in producing neuropathic pain and specifically whether C5a or assembly of the MAC is the prime effector of the pain, and 4) If complement activation alters excitability in dorsal horn neurons sufficiently to produce excitotoxic apoptosis. We will use this information to devise and test novel treatment strategies for somatic and facial neuropathic pain based either on blocking complement gene induction in microglia or complement cascade activation in the nervous system.