Microglia, Complement, and Pain

描述(申请人提供)：外周神经性疼痛由外周和中枢神经系统的不同变化引起，包括免疫系统和神经系统之间的相互作用。我们从芯片表达谱分析中发现，免疫基因在后角小胶质细胞中的激活是啮齿动物周围神经病理性疼痛模型的一个主要共同特征，最显著的包括局部诱导脊髓补体级联成分。此外，在神经病理性疼痛模型中，通过耗尽大鼠脊髓或突变小鼠的补体成分来阻断补体的级联反应，可以降低疼痛超敏反应。在此基础上，我们假设周围神经损伤导致损伤的感觉神经元产生一种信号，该信号被传递到三叉神经背角/脊髓核中传入的中央终末，在那里它作用于小胶质细胞以诱导补体基因。在背角浅层局部激活经典的补体级联通路，导致C5a过敏毒素的产生和膜攻击复合体(MAC)的组装。我们假设，C5a通过C5a受体改变小胶质细胞和神经元的功能，而MAC特异性地组装在那些不表达MAC组装的内源性抑制物CD59的神经元上，并通过增加神经元中的钙内流，增加它们的兴奋性和对凋亡的易感性。为了验证这一假说，我们建议确定：1)哪些外周刺激；活动，炎症或轴突损伤，诱导背角小胶质细胞中的补体基因；2)哪些细胞因子和趋化因子诱导小胶质细胞中的补体基因；3)补体级联在产生神经病理性疼痛中的作用，特别是C5a或MAC的组装是否是疼痛的主要效应者；以及4)补体激活是否充分改变了背角神经元的兴奋性，从而产生兴奋性细胞凋亡。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病理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.