Guo Wei, Wang Hu, Watanabe Mineo, Shimizu Kohei, Zou Shiping, LaGraize Stacey C, Wei Feng, Dubner Ronald, Ren Ke
Department of Biomedical Sciences, Program in Neuroscience, Dental School, University of Maryland, Baltimore, Maryland 21201, USA.
J Neurosci. 2007 May 30;27(22):6006-18. doi: 10.1523/JNEUROSCI.0176-07.2007.
The emerging literature implicates a role for glia/cytokines in persistent pain. However, the mechanisms by which these non-neural elements contribute to CNS activity-dependent plasticity and pain are unclear. Using a trigeminal model of inflammatory hyperalgesia, here we provide evidence that demonstrates a mechanism by which glia interact with neurons, leading to activity-dependent plasticity and hyperalgesia. In response to masseter inflammation, there was an upregulation of glial fibrillary acidic proteins (GFAPs), a marker of astroglia, and interleukin-1beta (IL-1beta), a prototype proinflammatory cytokine, in the region of the trigeminal nucleus specifically related to the processing of deep orofacial input. The activated astroglia exhibited hypertrophy and an increased level of connexin 43, an astroglial gap junction protein. The upregulated IL-1beta was selectively localized to astrocytes but not to microglia and neurons. Local anesthesia of the masseter nerve prevented the increase in GFAP and IL-1beta after inflammation, and substance P, a prototype neurotransmitter of primary afferents, induced similar increases in GFAP and IL-1beta, which was blocked by a nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester. Injection of IL-1 receptor antagonist and fluorocitrate, a glial inhibitor, attenuated hyperalgesia and NMDA receptor phosphorylation after inflammation. In vitro application of IL-1beta induced NR1 phosphorylation, which was blocked by an IL-1 receptor antagonist, a PKC inhibitor (chelerythrine), an IP3 receptor inhibitor (2-aminoethoxydiphenylborate), and inhibitors of phospholipase C [1-[6-((17b-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione] and phospholipase A2 (arachidonyltrifluoromethyl ketone). These findings provide evidence of astroglial activation by tissue injury, concomitant IL-1beta induction, and the coupling of NMDA receptor phosphorylation through IL-1 receptor signaling.
新兴文献表明神经胶质细胞/细胞因子在持续性疼痛中发挥作用。然而，这些非神经成分促成中枢神经系统活动依赖性可塑性和疼痛的机制尚不清楚。利用炎性痛觉过敏的三叉神经模型，我们在此提供证据，证明了一种神经胶质细胞与神经元相互作用的机制，该机制导致活动依赖性可塑性和痛觉过敏。针对咬肌炎症，在三叉神经核中与深部口面部输入处理特别相关的区域，星形胶质细胞标志物胶质纤维酸性蛋白（GFAP）和促炎细胞因子原型白细胞介素-1β（IL-1β）上调。活化的星形胶质细胞表现出肥大，并且星形胶质细胞缝隙连接蛋白连接蛋白43水平增加。上调的IL-1β选择性定位于星形胶质细胞，而非小胶质细胞和神经元。咬肌神经局部麻醉可防止炎症后GFAP和IL-1β增加，而初级传入神经的神经递质原型P物质可诱导GFAP和IL-1β出现类似增加，这被一氧化氮合酶抑制剂N（G）-硝基-L-精氨酸甲酯阻断。注射IL-1受体拮抗剂和胶质抑制剂氟柠檬酸可减轻炎症后的痛觉过敏和NMDA受体磷酸化。体外应用IL-1β可诱导NR1磷酸化，这被IL-1受体拮抗剂、PKC抑制剂（白屈菜红碱）、IP3受体抑制剂（2-氨基乙氧基二苯硼酸盐）以及磷脂酶C[1-[6-((17β-3-甲氧基雌甾-1,3,5(10)-三烯-17-基)氨基)己基]-1H-吡咯-2,5-二酮]和磷脂酶A2（花生四烯酰三氟甲基酮）抑制剂阻断。这些发现提供了组织损伤引起星形胶质细胞活化、伴随IL-1β诱导以及通过IL-1受体信号传导偶联NMDA受体磷酸化的证据。
