Remote activation of microglia and pro-inflammatory cytokines predict the onset and severity of below-level neuropathic pain after spinal cord injury in rats
Remote activation of microglia and pro-inflammatory cytokines predict the onset and severity of below-level neuropathic pain after spinal cord injury in rats
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DOI：
10.1016/j.expneurol.2008.04.009
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发表时间：
2008-08-01
影响因子：
5.3
通讯作者：
Basso, D. Michele
中科院分区：
文献类型：
--
作者：
Detloff, Megan Ryan;Fisher, Lesley C.;Basso, D. Michele
脊髓损伤（SCI）损害感觉系统，引起慢性异常性疼痛。周围神经损伤（PNI）后神经病理性疼痛的机制比中枢创伤后更广泛的研究。PNI后小胶质细胞活化、促炎细胞因子产生和p38 MAP激酶通路的活化可诱导at水平异常性疼痛。我们研究了胸中段脊髓损伤是否在损伤水平（腰髓; L5）以下引起类似的行为和细胞反应。重要的是，我们表明，L5和脊髓上中心之间的解剖连接保持完整的中度SCI后，允许直接比较一个完善的模型周围神经损伤。我们发现脊髓损伤引起的水平以下异常性疼痛与周围神经损伤引起的水平疼痛程度相似。此外，在L5脊髓中存在强大的小胶质细胞活化预测86%的大鼠的异常性疼痛。异常性疼痛大鼠L5背角p38 MAP激酶磷酸化水平也明显升高。对于SCI后低于水平的异常性疼痛，TNF-α和IL-1 β在L5背角中在7 dpo增加，并在35 dpo恢复到基线。有趣的是，IL-6在SCI后早期保持在正常水平，并在慢性时间点增加。SCI诱导的异常性疼痛后，丘脑中促炎细胞因子水平也增加。这些数据表明，远端小胶质细胞激活是关键的发展和维持低于水平的异常性疼痛后SCI。Fractalkine是一种已知的小胶质细胞激活剂，而星形胶质细胞不是低水平疼痛的主要调节剂。尽管远程小胶质细胞激活的机制尚不清楚，但这种反应可能是限制或预防人类SCI后神经性疼痛的可行靶点。(C)2008年爱思唯尔公司All rights reserved.
Spinal cord injury (SCI) impairs sensory systems causing chronic allodynia. Mechanisms underlying neuropathic pain have been more extensively studied following peripheral nerve injury (PNI) than after central trauma. Microglial activation, pro-inflammatory cytokine production and activation of p38 MAP kinase pathways may induce at-level allodynia following PNI. We investigated whether midthoracic SCI elicits similar behavioral and cellular responses below the level of injury (lumbar spinal cord; L5). Importantly, we show that anatomical connections between L5 and supraspinal centers remain intact after moderate SCI allowing direct comparison to a well-established model of peripheral nerve injury. We found that SCI elicits below-level allodynia of similar magnitude to at-level pain caused by a peripheral nerve injury. Moreover, the presence of robust microglial activation in L5 cord predicted allodynia in 86% of rats. Also increased phosphorylation of p38 MAP kinase occurred in the L5 dorsal horn of allodynic rats. For below-level allodynia after SCI, TNF-alpha and IL-1 beta increased in the L5 dorsal horn by 7 dpo and returned to baseline by 35 dpo. Interestingly, IL-6 remains at normal levels early after SCI and increases at chronic time points. Increased levels of pro-inflammatory cytokines also occurred in the thalamus after SCI-induced allodynia. These data suggest that remote microglial activation is pivotal in the development and maintenance of below-level allodynia after SCI. Fractalkine, a known activator of microglia, and astrocytes were not primary modulators of below-level pain. Although the mechanisms of remote microglial activation are unknown, this response may be a viable target for limiting or preventing neuropathic pain after SCI in humans. (C) 2008 Elsevier Inc. All rights reserved.