Spared Nerve Injury Increases the Expression of Microglia M1 Markers in the Prefrontal Cortex of Rats and Provokes Depression-Like Behaviors.
Spared Nerve Injury Increases the Expression of Microglia M1 Markers in the Prefrontal Cortex of Rats and Provokes Depression-Like Behaviors.
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DOI：
10.3389/fnins.2017.00209
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发表时间：
2017
影响因子：
4.3
通讯作者：
Zhou ZQ
中科院分区：
文献类型：
--
作者：
Xu N;Tang XH;Pan W;Xie ZM;Zhang GF;Ji MH;Yang JJ;Zhou MT;Zhou ZQ
在临床实践中，疼痛和抑郁经常共存，但其潜在机制仍有待确定。小胶质细胞活化和随后的促炎反应在神经性疼痛和抑郁症的发展中起着至关重要的作用。小胶质细胞极化为促炎M1或抗炎M2表型的过程通常发生在神经炎症期间。然而，目前尚不清楚M1/M2小胶质细胞极化是否参与了备用神经损伤（SNI）引起的神经病理性疼痛。本研究采用机械性缩足阈、强迫游泳试验、蔗糖偏好试验和旷场试验。小胶质细胞标志物包括离子化钙结合衔接分子1（Iba 1）、分化簇11b（CD 11b），M1标志物包括CD 68、诱导型一氧化氮合酶（iNOS）、白细胞介素-1 β（IL-1β）、IL-6、肿瘤坏死因子-α（TNF-α）、8-羟基-2-脱氧鸟苷（8-OH-dG），以及M2标志物包括CD 206、腺苷酸酶1（Arg 1）、于SNI后第14天测定前额叶皮质IL-4含量。结果表明，SNI可引起大鼠机械性异常性疼痛和抑郁样行为，并可增加前额叶皮质小胶质细胞标志物（Iba 1、CD 11b）和M1标志物（CD 68、iNOS、IL-1β、TNF-α和8-OH-dG）的表达。值得注意的是，二甲胺四环素给药逆转了这些异常。此外，米诺环素还促进M2小胶质细胞极化，如通过上调CD 206和Arg 1所证明的。总之，我们的研究数据表明，SNI可以导致抑郁样行为，而M1极化和随之而来的促炎细胞因子的过度产生在神经病理性疼痛的发病机制中起着关键作用。数据进一步表明，通过抑制M1极化来调节炎症可能是治疗神经性疼痛的一种策略，并且可能会预防神经性疼痛诱导的抑郁症状的诱导。
Pain and depression are frequently co-existent in clinical practice, yet the underlying mechanisms remain largely to be determined. Microglia activation and subsequent pro-inflammatory responses play a crucial role in the development of neuropathic pain and depression. The process of microglia polarization to the pro-inflammatory M1 or anti-inflammatory M2 phenotypes often occurs during neuroinflammation. However, it remains unclear whether M1/M2 microglia polarization is involved in the neuropathic pain induced by spared nerve injury (SNI). In the present study, the mechanical withdrawal threshold, forced swim test, sucrose preference test, and open field test were performed. The levels of microglia markers including ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation 11b (CD11b), M1 markers including CD68, inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-a (TNF-α), 8-hydroxy-2-deoxyguanosine (8-OH-dG), and M2 markers including CD206, arginase 1 (Arg1), IL-4 in the prefrontal cortex were determined on day 14 after SNI. The results showed that SNI produced mechanical allodynia and depressive-like behaviors, and also increased the expressions of microglia markers (Iba1, CD11b) and M1 markers (CD68, iNOS, IL-1β, TNF-α, and 8-OH-dG) in the prefrontal cortex. Notably, minocycline administration reversed these abnormalities. In addition, minocycline also promoted M2 microglia polarization as evidenced by up-regulation of CD206 and Arg1. In conclusion, data from our study suggest that SNI can lead to depression-like behaviors, while M1 polarization and consequent overproduction of pro-inflammatory cytokines plays a key role in the pathogenesis of neuropathic pain. The data furthermore indicate that modulation of inflammation by inhibition of M1 polarization could be a strategy for treatment of neuropathic pain, and might prevent the induction of neuropathic pain-induced depression symptoms.