ATP mediates neuropathic pain of neuromyelitis optica spectrum disorder via microglial activation

Intractable neuropathic pain is recognized as a common symptom of neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism of NMOSD pain remains to be elucidated. Here, we established NMOSD pain model by injecting anti-AQP4 recombinant autoantibodies (AQP4-Ab) generated from NMOSD patient’s plasmablasts into rat spinal cords and confirmed the development of mechanical allodynia. AQP4-Ab mediated extracellular ATP release from astrocytes and pharmacological inhibition of ATP receptor reversed mechanical allodynia in NMOSD pain model. Furthermore, transcriptome analysis revealed microglia activation and IL-1β elevation in NMOSD spinal cord. Inhibition of microglia activation and neutralization of IL-1β also attenuated neuropathic pain in NMOSD rat model. In addition, the human CSF ATP concentration was significantly higher in the acute and remission phase of NMOSD than in multiple sclerosis and other neurological disorder patients. These findings indicate ATP, microglial activation and IL-1β secretion orchestrates the pathogenesis of NMOSD neuropathic pain.难治性神经性疼痛被认为是视神经脊髓炎谱系疾病（neuromyelitis optica spectrum disorder, NMOSD）的常见症状。然而，视神经脊髓炎谱系疾病相关性疼痛的潜在发病机制仍有待阐明。本研究通过将视神经脊髓炎谱系疾病患者浆母细胞来源的抗AQP4重组自身抗体（anti-AQP4 recombinant autoantibodies, AQP4-Ab）注入大鼠脊髓，成功构建了视神经脊髓炎谱系疾病疼痛模型，并证实了机械性痛觉超敏的发生。AQP4-Ab可介导星形胶质细胞释放细胞外ATP，而ATP受体的药理学抑制可逆转该模型中的机械性痛觉超敏。此外，转录组分析显示，视神经脊髓炎谱系疾病模型大鼠脊髓中存在小胶质细胞活化及IL-1β水平升高；抑制小胶质细胞活化并中和IL-1β，同样可减轻模型大鼠的神经性疼痛。另外，相较于多发性硬化及其他神经系统疾病患者，视神经脊髓炎谱系疾病患者在急性期与缓解期的脑脊液（cerebrospinal fluid, CSF）ATP浓度均显著升高。上述研究结果表明，ATP、小胶质细胞活化及IL-1β分泌共同介导了视神经脊髓炎谱系疾病相关性神经性疼痛的发病机制。