Laboratory of Neuroimmunology and Developmental Origins of Disease-NIDOD, University Medical Center Utrecht, Utrecht, 3584 EA, The Netherlands.
J Neuroinflammation. 2012 Jun 25;9:143. doi: 10.1186/1742-2094-9-143.
Chronic pain is often associated with microglia activation in the spinal cord. We recently showed that microglial levels of the kinase G protein-coupled receptor kinase (GRK)2 are reduced in models of chronic pain. We also found that mice with a cell-specific reduction of around 50% in GRK2 level in microglia/macrophages (LysM-GRK2+/- mice) develop prolonged inflammatory hyperalgesia concomitantly with ongoing spinal microglia/macrophage activation. The microRNA miR-124 is thought to keep microglia/macrophages in brain and spinal cord in a quiescent state. In the present study, we investigated the contribution of miR-124 to regulation of hyperalgesia and microglia/macrophage activation in GRK2-deficient mice. In addition, we investigated the effect of miR-124 on chronic inflammatory and neuropathic pain in wild-type (WT) mice.
Hyperalgesia was induced by intraplantar IL-1β in WT and LysM-GRK2+/- mice. We determined spinal cord microglia/macrophage miR-124 expression and levels of pro-inflammatory M1 and anti-inflammatory M2 activation markers. The effect of intrathecal miR-124 treatment on IL-1β-induced hyperalgesia and spinal M1/M2 phenotype, and on carrageenan-induced and spared nerve injury-induced chronic hyperalgesia in WT mice was analyzed.
Transition from acute to persistent hyperalgesia in LysM-GRK2+/- mice is associated with reduced spinal cord microglia miR-124 levels. In our LysM-GRK2+/- mice, there was a switch towards a pro-inflammatory M1 phenotype together with increased pro-inflammatory cytokine production. Intrathecal administration of miR-124 completely prevented the transition to persistent pain in response to IL-1β in LysM-GRK2+/- mice. The miR-124 treatment also normalized expression of spinal M1/M2 markers of LysM-GRK2+/- mice. Moreover, intrathecal miR-124 treatment reversed the persistent hyperalgesia induced by carrageenan in WT mice and prevented development of mechanical allodynia in the spared nerve injury model of chronic neuropathic pain in WT mice.
We present the first evidence that intrathecal miR-124 treatment can be used to prevent and treat persistent inflammatory and neuropathic pain. In addition, we show for the first time that persistent hyperalgesia in GRK2-deficient mice is associated with an increased ratio of M1/M2 type markers in spinal cord microglia/macrophages, which is restored by miR-124 treatment. We propose that intrathecal miR-124 treatment might be a powerful novel treatment for pathological chronic pain with persistent microglia activation.
慢性疼痛通常与脊髓中小胶质细胞的激活有关。我们最近发现，慢性疼痛模型中小胶质细胞中的激酶 G 蛋白偶联受体激酶 (GRK)2 水平降低。我们还发现，小胶质细胞/巨噬细胞中 GRK2 水平降低约 50%的特异性敲除小鼠 (LysM-GRK2+/- 小鼠) 同时伴有脊髓小胶质细胞/巨噬细胞持续激活，表现出延长的炎症性痛觉过敏。miR-124 被认为可使大脑和脊髓中的小胶质细胞/巨噬细胞保持静止状态。在本研究中，我们研究了 miR-124 对 GRK2 缺陷型小鼠中痛觉过敏和小胶质细胞/巨噬细胞激活的调节作用。此外，我们还研究了 miR-124 对野生型 (WT) 小鼠慢性炎症性和神经性疼痛的影响。
通过足底注射白细胞介素-1β (IL-1β) 在 WT 和 LysM-GRK2+/- 小鼠中诱导痛觉过敏。我们测定脊髓小胶质细胞/巨噬细胞 miR-124 的表达水平和促炎 M1 型和抗炎 M2 型激活标志物的水平。分析鞘内给予 miR-124 对 WT 小鼠中 IL-1β 诱导的痛觉过敏、脊髓 M1/M2 表型以及角叉菜胶诱导和 spared 神经损伤诱导的慢性痛觉过敏的影响。
LysM-GRK2+/- 小鼠中从急性痛觉过敏向持续性痛觉过敏的转变与脊髓小胶质细胞 miR-124 水平降低有关。在我们的 LysM-GRK2+/- 小鼠中，出现了向促炎 M1 表型的转变，同时促炎细胞因子的产生增加。鞘内给予 miR-124 可完全防止 LysM-GRK2+/- 小鼠对 IL-1β 反应时向持续性疼痛的转变。miR-124 治疗还使 LysM-GRK2+/- 小鼠的脊髓 M1/M2 标志物表达正常化。此外，鞘内给予 miR-124 可逆转 WT 小鼠中角叉菜胶诱导的持续性痛觉过敏，并防止 WT 小鼠 spared 神经损伤模型中慢性神经性疼痛的机械性痛觉过敏的发展。
我们首次证明鞘内给予 miR-124 可用于预防和治疗持续性炎症性和神经性疼痛。此外，我们首次表明，GRK2 缺陷型小鼠的持续性痛觉过敏与脊髓小胶质细胞/巨噬细胞中 M1/M2 型标志物的比例增加有关，而 miR-124 治疗可恢复这一比例。我们提出，鞘内给予 miR-124 可能是治疗持续性小胶质细胞激活相关病理性慢性疼痛的一种强有力的新方法。
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