Sawada Atsushi, Niiyama Yukitoshi, Ataka Koji, Nagaishi Kanna, Yamakage Michiaki, Fujimiya Mineko
Department of Anesthesiology, Sapporo Medical University, School of Medicine, Sapporo, Japan Department of Anatomy, Sapporo Medical University, School of Medicine, Sapporo, Japan.
Pain. 2014 Sep;155(9):1762-1772. doi: 10.1016/j.pain.2014.05.031. Epub 2014 Jun 4.
Chronic neuropathic pain causes abnormal sensitivities such as hyperalgesia and allodynia, and emotional abnormalities such as anxiety and depression. Although spinal cord microglia are involved in abnormal sensitivity to neuropathic pain, no previous studies have examined the mechanism of neuropathic pain-induced anxiety. Here, we examined the involvement of bone marrow (BM)-derived microglia aggregated in the amygdalae of mice with chronic neuropathic pain in the development of anxiety-like behavior. We prepared partial sciatic nerve ligations (PSNL) in mice that received bone marrow transplantation from green fluorescent protein (GFP)-Tg mice after irradiation with head protection, and examined GFP-positive microglia in the central nuclei of the amygdalae (CeA). On day 28 after PSNL, BM-derived microglia aggregated in the CeA concurrent with anxiety-like behavior. BM-derived microglia in the CeA highly expressed interleukin (IL)-1β and C-C chemokine receptor type 2 (CCR2). In addition, neurons in the CeA highly expressed monocyte chemotactic protein-1 (MCP-1), a ligand for CCR2, in PSNL-treated mice compared to sham-operated mice, suggesting that the MCP-1/CCR2 axis is involved in the recruitment of BM-derived microglia. Oral administration of a CCR2 antagonist decreased the number of BM-derived microglia in the CeA, and successfully reversed the anxiety-like behavior and hypersensitivity to mechanical stimuli in PSNL-treated mice. Microinjections of an IL-1β receptor antagonist directly into the CeA successfully reversed the anxiety-like behavior in the PSNL-treated mice even though the neuropathic pain persisted. These results suggest that the recruitment of BM-derived microglia to the CeA via the MCP-1/CCR2 axis and neuron-microglia interactions might be important in the pathogenesis of neuropathic pain-induced anxiety.
慢性神经性疼痛会导致痛觉过敏和异常性疼痛等异常敏感性，以及焦虑和抑郁等情绪异常。尽管脊髓小胶质细胞参与了对神经性疼痛的异常敏感性，但之前尚无研究探讨神经性疼痛诱发焦虑的机制。在此，我们研究了慢性神经性疼痛小鼠杏仁核中聚集的骨髓源性小胶质细胞在焦虑样行为发生过程中的作用。我们对接受头部保护照射后来自绿色荧光蛋白（GFP）转基因小鼠骨髓移植的小鼠进行部分坐骨神经结扎（PSNL），并检查杏仁核中央核（CeA）中的GFP阳性小胶质细胞。PSNL后第28天，骨髓源性小胶质细胞聚集在CeA中，同时出现焦虑样行为。CeA中的骨髓源性小胶质细胞高表达白细胞介素（IL）-1β和C-C趋化因子受体2型（CCR2）。此外，与假手术小鼠相比，PSNL处理小鼠的CeA中的神经元高表达单核细胞趋化蛋白-1（MCP-1），它是CCR2的配体，这表明MCP-1/CCR2轴参与了骨髓源性小胶质细胞的募集。口服CCR2拮抗剂可减少CeA中骨髓源性小胶质细胞的数量，并成功逆转PSNL处理小鼠的焦虑样行为和对机械刺激的超敏反应。即使神经性疼痛持续存在，将IL-1β受体拮抗剂直接微量注射到CeA中也成功逆转了PSNL处理小鼠的焦虑样行为。这些结果表明，通过MCP-1/CCR2轴将骨髓源性小胶质细胞募集到CeA以及神经元与小胶质细胞的相互作用可能在神经性疼痛诱发焦虑的发病机制中起重要作用。
