Spinal versus brain microglial and macrophage activation traits determine the differential neuroinflammatory responses and analgesic effect of minocycline in chronic neuropathic pain
Spinal versus brain microglial and macrophage activation traits determine the differential neuroinflammatory responses and analgesic effect of minocycline in chronic neuropathic pain
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DOI：
10.1016/j.bbi.2016.05.021
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发表时间：
2016-11-01
影响因子：
15.1
通讯作者：
Tian, Li
中科院分区：
文献类型：
--
作者：
Li, Zhilin;Wei, Hong;Tian, Li
大量证据表明，小胶质细胞/巨噬细胞参与慢性神经性疼痛。然而，小胶质细胞/巨噬细胞激活的时空特征及其与疼痛相关的作用仍然难以捉摸。本研究评估了大鼠腰脊髓（SC）和前额叶皮质（PFC）中小胶质细胞/巨噬细胞及其亚型，以及米诺环素在余留神经损伤（SNI）后不同阶段的镇痛-焦虑作用。虽然SNI组术后第3天（POD）后脊髓小胶质细胞/巨噬细胞数量增加，但SNI组大鼠的促炎MHCII+脊髓小胶质细胞/巨噬细胞的丰度出乎意料地低于POD21组。相比之下，SNI大鼠PFC中抗炎CD172a (SIRP α)（+）小胶质细胞/巨噬细胞含量较少。有趣的是，在幼稚大鼠中，SC中CD11b/c、MHCII和MHCII+/CD172a（+）比值的小胶质/巨噬细胞表达高于皮层。SNI大鼠脊髓背角和背根神经节中参与抗炎、吞噬、补体活化和M2小胶质/巨噬细胞极化的多个免疫基因表达上调，而PFC中下调。此外，从PODO开始，每天鞘内二甲胺四环素治疗两周，在POD3之前最有力地缓解了机械性异常性痛，并减轻了POD9时的焦虑。尽管二甲胺四环素对脊髓MHCII小胶质细胞/巨噬细胞的抑制作用一直持续到POD13，但对皮质小胶质细胞/巨噬细胞却没有作用，这表明仅抑制脊髓炎症可能不足以缓解慢性期的集中性疼痛。综上所述，我们的数据提供了第一个证据，表明基底小胶质/巨噬细胞特征是SNI和米诺环素治疗差异区域特异性反应的基础，并表明有效靶向脊髓和脑炎症的药物治疗可能更有效地治疗慢性神经性疼痛。(C) 2016 Elsevier Inc.版权所有。
Substantial evidence indicates involvement of microglia/macrophages in chronic neuropathic pain. However, the temporal-spatial features of microglial/macrophage activation and their pain-bound roles remain elusive. Here, we evaluated microglia/macrophages and the subtypes in the lumbar spinal cord (SC) and prefrontal cortex (PFC), and analgesic-anxiolytic effect of minocycline at different stages following spared nerve injury (SNI) in rats. While SNI enhanced the number of spinal microglia/macrophages since post-operative day (POD)3, pro-inflammatory MHCII+ spinal microglia/macrophages were unexpectedly less abundant in SNI rats than shams on POD21. By contrast, less abundant anti-inflammatory CD172a (SIRP alpha)(+) microglia/macrophages were found in the PFC of SNI rats. Interestingly in naive rats, microglial/macrophage expression of CD11b/c, MHCII and MHCII+/CD172a(+) ratio were higher in the SC than the cortex. Consistently, multiple immune genes involved in anti-inflammation, phagocytosis, complement activation and M2 microglial/macrophage polarization were upregulated in the spinal dorsal horn and dorsal root ganglia but downregulated in the PFC of SNI rats. Furthermore, daily intrathecal minocycline treatment starting from PODO for two weeks alleviated mechanical allodynia most robustly before POD3 and attenuated anxiety on POD9. Although minocycline dampened spinal MHCII microglia/macrophages until POD13, it failed to do so on cortical microglia/macrophages, indicating that dampening only spinal inflammation may not be enough to alleviate centralized pain at the chronic stage. Taken together, our data provide the first evidence that basal microglial/macrophage traits underlie differential region-specific responses to SNI and minocycline treatment, and suggest that drug treatment efficiently targeting not only spinal but also brain inflammation may be more effective in treating chronic neuropathic pain. (C) 2016 Elsevier Inc. All rights reserved.