Levin Margaret E, Jin Jason G, Ji Rui-Ru, Tong Jeifei, Pomonis James D, Lavery Daniel J, Miller Scott W, Chiang Lillian W
Galenea, 300 Technology Square 2nd Floor, Cambridge, MA 02139, USA MaxyBio Corporation, 675 U.S. Highway One, North Brunswick, NJ 08902, USA Bristol Myers Squibb, 311 Pennington Rocky Hill, Pennington, NJ 08534, USA Program in Molecular Structure and Function, Hospital for Sick Children, MaRS East Tower, Toronto, Ont., Canada M5G 1L7 Empi, Inc., 599 Cardigan Rd, St. Paul, MN 55126, USA Chromocell Corporation, 675 U.S. Highway One, North Brunswick, NJ 0890, USA Wyeth Research, 865 Ridge Road, Monmouth Junction, NJ 08852, USA Aestus Therapeutics, Inc., 675 U.S. Highway One, No. Brunswick, NJ 0890, USA.
Pain. 2008 Jul;137(1):182-201. doi: 10.1016/j.pain.2007.11.005. Epub 2007 Dec 21.
Neuroinflammatory and neuroimmune mechanisms, as exemplified by infiltrating immune cells and activation of resident endothelial/glial cells, respectively, are known to be involved in the establishment and maintenance of chronic pain. An immune system pathway that may be involved in the activation of both immune and glial cells is complement. The complement pathway is made up of a large number of distinct plasma proteins which react with one another to opsonize pathogens and induce a series of inflammatory responses to help fight infection. Cleaved products and complexes produced by complement activation are responsible for a range of effects including mediation of immune infiltration, activation of phagocytes, opsonization/lysis of pathogens and injured cells, and production of vasoactive amines such as histamine and serotonin. Gene-expression microarray-analysis performed on the rat spinal nerve ligation (SNL) model of neuropathic pain revealed that multiple complement components including the C1 inhibitor, C1q alpha, beta, and gamma, C1r, C1s, C2, C3, C4, C7, and factors B, D, H, and P, were up-regulated while DAF was down-regulated. Regulation of C3 and DAF was confirmed by real-time RT-PCR and in situ hybridization. To test the hypothesis that complement plays a role in neuropathic pain, SNL rats were treated with cobra venom factor (CVF) to deplete plasma of complement component C3. Pain behavior was significantly attenuated in SNL rats treated with CVF as was complement activity at the ipsilateral dorsal root ganglia. Our results suggest the complement pathway might be a novel target for the development of neuropathic pain therapeutics.
神经炎症和神经免疫机制，分别以浸润的免疫细胞和驻留的内皮/神经胶质细胞的激活为代表，已知参与慢性疼痛的建立和维持。补体是一种可能参与免疫细胞和神经胶质细胞激活的免疫系统途径。补体途径由大量不同的血浆蛋白组成，这些蛋白相互反应以调理病原体并诱导一系列炎症反应以帮助对抗感染。补体激活产生的裂解产物和复合物负责一系列效应，包括介导免疫浸润、激活吞噬细胞、调理/裂解病原体和受损细胞，以及产生组胺和5-羟色胺等血管活性胺。对神经性疼痛的大鼠脊神经结扎（SNL）模型进行的基因表达微阵列分析显示，包括C1抑制剂、C1qα、β和γ、C1r、C1s、C2、C3、C4、C7以及因子B、D、H和P在内的多种补体成分上调，而衰变加速因子（DAF）下调。通过实时逆转录聚合酶链反应（RT-PCR）和原位杂交证实了C3和DAF的调节。为了检验补体在神经性疼痛中起作用的假设，用眼镜蛇毒因子（CVF）处理SNL大鼠以耗尽血浆中的补体成分C3。用CVF处理的SNL大鼠的疼痛行为明显减轻，同侧背根神经节的补体活性也是如此。我们的结果表明补体途径可能是开发神经性疼痛治疗方法的一个新靶点。
