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研究表明小胶质细胞参与了神经病理性疼痛,但是受损的感觉神经元如何调节小胶质细胞仍不清楚。本研究发现:外周神经损伤诱导受损的感觉神经元表达集落刺激因子1(colony-stimulating factor1,CSF1)。CSF1被运输至脊髓,作用于小胶质细胞上的CSF1受体(CSF1 receptor,CSF1R)。感觉神经元中Csf1缺失完全阻断了神经损伤诱导的机械性痛觉过敏,并抑制了小胶质细胞活化和增殖。相反,鞘内注射CSF1诱导了机械性痛觉过敏的产生和小胶质细胞增殖。神经损伤也增加了运动神经元中CSF1表达,促进腹角小胶质细胞活化和增殖。CSF1R的下游是小胶质细胞膜接头蛋白12(membrane adaptor protein12,DAP12)。DAP12是神经损伤或鞘内注射CSF1诱导小胶质细胞内疼痛相关基因表达上调和随后的疼痛产生的关键分子,但小胶质细胞增殖并不依赖DAP12。因此,CSF1和DAP12都可能成为药物治疗神经病理性疼痛的潜在靶点。
Studies have shown that microglia are involved in neuropathic pain, but how damaged sensory neurons regulate microglia remains unclear. The present study found that peripheral nerve injury induces colony-stimulating factor 1 (CSF1) expression in impaired sensory neurons. CSF1 is transported to the spinal cord and acts on the CSF1 receptor (CSF1R) on microglia. Csf1 knockdown in sensory neurons completely blocked mechanical allodynia induced by nerve injury and inhibited microglial activation and proliferation. In contrast, intrathecal injection of CSF1 induces the production of mechanical hyperalgesia and microglial proliferation. Nerve damage also increases the expression of CSF1 in motor neurons, promoting the activation and proliferation of the microglia in the ventral horn. Downstream of CSF1R is membrane adapter protein 12 (DAP12). DAP12 is a key molecule for nerve injury or intrathecal CSF1-induced upregulation of pain-associated genes in microglia and subsequent pain production, but microglial proliferation is not dependent on DAP12. Therefore, both CSF1 and DAP12 may be potential targets for drug treatment of neuropathic pain.