Visualization of chemokine receptor activation in transgenic mice reveals peripheral activation of CCR2 receptors in states of neuropathic pain.
Visualization of chemokine receptor activation in transgenic mice reveals peripheral activation of CCR2 receptors in states of neuropathic pain.
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DOI：
10.1523/jneurosci.0485-09.2009
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发表时间：
2009-06-24
期刊：
影响因子：
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通讯作者：
Miller RJ
中科院分区：
文献类型：
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作者：
Jung H;Bhangoo S;Banisadr G;Freitag C;Ren D;White FA;Miller RJ
CCR 2趋化因子受体信号转导已涉及多种类型的神经病理学的产生，包括神经性疼痛。例如，ccr 2敲除小鼠对神经性疼痛的建立具有抗性，而过表达其配体单核细胞趋化蛋白-1（MCP 1;也称为CCL 2）的小鼠显示出增强的疼痛敏感性。然而，在神经性疼痛状态下，CCR 2受体活化是否发生在中枢或外周神经系统中尚不清楚。我们开发了一种新的方法，通过产生双转基因报告小鼠，其中趋化因子受体CCR 2及其配体MCP 1分别被荧光蛋白增强的绿色荧光蛋白和单体红色荧光蛋白-1标记，用于可视化体内CCR 2受体活化。在急性炎症和实验性自身免疫性脑脊髓炎等条件下的CCR 2受体活化可以通过使用这些小鼠忠实地可视化。我们研究了神经病理性疼痛脱髓鞘损伤模型中CCR 2受体的激活状态，发现MCP 1诱导的CCR 2受体激活主要发生在周围神经系统，包括受损的周围神经和背根神经节。这些数据解释了在这些情况下外周给药的CCR 2拮抗剂的快速抗伤害感受作用，表明CCR 2拮抗剂可通过抑制外周中的CCR 2受体活化来改善疼痛。在这里开发的方法可视化CCR 2受体激活在体内可以扩展到G-蛋白偶联受体（GPCR）一般，将是有价值的研究细胞间GPCR介导的通信在体内。
CCR2 chemokine receptor signaling has been implicated in the generation of diverse types of neuropathology, including neuropathic pain. For example, ccr2 knock-out mice are resistant to the establishment of neuropathic pain, and mice overexpressing its ligand, monocyte chemoattractant protein-1 (MCP1; also known as CCL2), show enhanced pain sensitivity. However, whether CCR2 receptor activation occurs in the central or peripheral nervous system in states of neuropathic pain has not been clear. We developed a novel method for visualizing CCR2 receptor activation in vivo by generating bitransgenic reporter mice in which the chemokine receptor CCR2 and its ligand MCP1 were labeled by the fluorescent proteins enhanced green fluorescent protein and monomeric red fluorescent protein-1, respectively. CCR2 receptor activation under conditions such as acute inflammation and experimental autoimmune encephalomyelitis could be faithfully visualized by using these mice. We examined the status of CCR2 receptor activation in a demyelination injury model of neuropathic pain and found that MCP1-induced CCR2 receptor activation mainly occurred in the peripheral nervous system, including the injured peripheral nerve and dorsal root ganglia. These data explain the rapid antinociceptive effects of peripherally administered CCR2 antagonists under these circumstances, suggesting that CCR2 antagonists may ameliorate pain by inhibiting CCR2 receptor activation in the periphery. The method developed here for visualizing CCR2 receptor activation in vivo may be extended to G-protein-coupled receptors (GPCRs) in general and will be valuable for studying intercellular GPCR-mediated communication in vivo.