Jiangsu Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China.
Jiangsu Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China; Brain Institute, the Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, China.
Brain Res Bull. 2020 Mar;156:58-66. doi: 10.1016/j.brainresbull.2020.01.004. Epub 2020 Jan 9.
Growing evidence suggests a critical role of astrocytes for pain regulation. The water channel protein aquaporin 4 (AQP4), a functional regulator of astrocytes, is involved in various neurological disorders. However, the pathophysiological roles of AQP4 in pain conditions remain unclear. In the present study, we investigated the effect of AQP4 gene knockout in central sensitization induced by complete Freund's adjuvant (CFA). The behavioral analysis revealed that mechanical allodynia and thermal hyperalgesia were more severe in AQP4 null mice than those of wild-type controls over the course of 11 days following CFA intraplantar injection. CFA caused activation of astrocytes with upregulated expression levels of AQP4 and glutamate transporter 1 (GLT1) in the dorsal horn of the spinal cord. AQP4 deficiency reduced GLT1 up-regulation, causing persistent expression of the neuronal activation marker Fos within superficial dorsal horn neurons, including glutamatergic neurons. However, AQP4 deletion did not affect CFA-evoked proinflammatory cytokine expression in the spinal cord. Together, these results have shown that AQP4 absence intensifies CFA-induced spinal central sensitization, which is associated with reduced compensatory up-regulation of GLT1, subsequently increasing glutamatergic overexcitation. Therefore, targeting spinal cord AQP4 may serve as a potential strategy for treatment of peripheral inflammation-evoked hyperalgesia.
越来越多的证据表明星形胶质细胞在疼痛调节中起着关键作用。水通道蛋白 4（AQP4）是星形胶质细胞的一种功能调节剂，参与多种神经疾病。然而，AQP4 在疼痛情况下的病理生理作用仍不清楚。在本研究中，我们研究了 AQP4 基因敲除对完全弗氏佐剂（CFA）诱导的中枢敏化的影响。行为分析表明，在 CFA 足底注射后 11 天内，AQP4 缺失小鼠的机械性痛觉过敏和热痛觉过敏比野生型对照小鼠更为严重。CFA 导致脊髓背角星形胶质细胞激活，AQP4 和谷氨酸转运体 1（GLT1）表达水平上调。AQP4 缺乏减少了 GLT1 的上调，导致浅层背角神经元（包括谷氨酸能神经元）中神经元激活标志物 Fos 的持续表达。然而，AQP4 缺失并不影响脊髓中 CFA 诱导的促炎细胞因子表达。总之，这些结果表明 AQP4 缺失加剧了 CFA 诱导的脊髓中枢敏化，这与 GLT1 的代偿性上调减少有关，随后增加了谷氨酸能过度兴奋。因此，靶向脊髓 AQP4 可能是治疗外周炎症引起的痛觉过敏的一种潜在策略。
