Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2
Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2
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DOI：
10.1073/pnas.1331358100
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发表时间：
2003-06-24
影响因子：
11.1
通讯作者：
Forrest, MJ
中科院分区：
文献类型：
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作者：
Abbadie, C;Lindia, JA;Forrest, MJ
缺乏趋化因子受体趋化性细胞因子受体2（CCR 2）的小鼠具有响应于各种炎性刺激的单核细胞募集的显著减弱和脱髓鞘疾病模型中的炎性病变的减少。在本研究中，我们比较了CCR 2基因敲除小鼠和野生型小鼠在炎症和神经病理性疼痛模型中的伤害性反应。在急性疼痛测试中，CCR 2敲除小鼠和野生型小鼠的反应是等同的。在炎性疼痛模型中，CCR 2敲除小鼠表现出足底福尔马林诱发疼痛反应的第2阶段减少70%，但足底弗氏佐剂（CFA）后机械性异常性疼痛仅适度（20-30%）且无显著减少。在神经性疼痛模型中，CCR 2基因敲除小鼠的机械性异常性疼痛完全消失。CFA给药诱导皮肤中CCR 2 mRNA显著上调，坐骨神经和背根神经节（DRG）中度增加。在响应神经结扎，CCR 2 mRNA的持续和显着的上调是明显的神经和DRG。雪旺氏细胞的破坏，在响应神经损伤导致CCR 2阳性的单核细胞/巨噬细胞的浸润不仅到神经瘤，但也到DRG。慢性疼痛还导致脊髓中出现活化的CCR 2阳性小胶质细胞。总的来说，这些数据表明，外周和神经组织中巨噬细胞和小胶质细胞的募集和活化可能有助于炎症和神经性疼痛状态。因此，CCR 2受体的阻断可以提供用于治疗慢性疼痛的新的治疗方式。
Mice lacking the chemokine receptor chemotactic cytokine receptor 2 (CCR2) have a marked attenuation of monocyte recruitment in response to various inflammatory stimuli and a reduction of inflammatory lesions in models of demyelinating disease. In the present study, we compared nociceptive responses in inflammatory and neuropathic models of pain in CCR2 knockout and wildtype mice. In acute pain tests, responses were equivalent in CCR2 knockout and wild-type mice. In models of inflammatory pain, CCR2 knockout mice showed a 70% reduction in phase 2 of the intraplantar formalin-evoked pain response but only a modest (20-30%) and nonsignificant reduction of mechanical allodynia after intraplantar Freund's adjuvant (CFA). In a model of neuropathic pain, the development of mechanical allodynia was totally abrogated in CCR2 knockout mice. CFA administration induced marked up-regulation of CCR2 mRNA in the skin and a moderate increase in the sciatic nerve and dorsal root ganglia (DRG). In response to nerve ligation, persistent and marked up-regulation of CCR2 mRNA was evident in the nerve and DRG. Disruption of Schwann cells in response to nerve lesion resulted in infiltration of CCR2-positive monocytes/macrophages not only to the neuroma but also to the DRG. Chronic pain also resulted in the appearance of activated CCR2-positive microglia in the spinal cord. Collectively, these data suggest that the recruitment and activation of macrophages and microglia peripherally and in neural tissue may contribute to both inflammatory and neuropathic pain states. Accordingly, blockade of the CCR2 receptor may provide a novel therapeutic modality for the treatment of chronic pain.