Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee University, Seoul 02453, Republic of Korea.
Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee University, Seoul 02453, Republic of Korea; Department of Biomedical Science, Kyung Hee University, Seoul 02447, Republic of Korea.
Exp Neurol. 2023 Dec;370:114576. doi: 10.1016/j.expneurol.2023.114576. Epub 2023 Oct 18.
After spinal cord injury (SCI), the control of activated glial cells such as microglia and astrocytes has emerged as a promising strategy for neuropathic pain management. However, signaling mechanism involved in glial activation in the process of neuropathic pain development and maintenance after SCI is not well elucidated. In this study, we investigated the potential role and mechanism of the JAK2/STAT3 pathway associated with glial cell activation in chronic neuropathic pain development and maintenance after SCI. One month after contusive SCI, the activation of JAK2/STAT3 pathway was markedly upregulated in both microglia and astrocyte in nociceptive processing regions of the lumbar spinal cord. In addition, both mechanical allodynia and thermal hyperalgesia was significantly inhibited by a JAK2 inhibitor, AG490. In particular, AG490 treatment inhibited both microglial and astrocyte activation in the lumbar (L) 4-5 dorsal horn and significantly decreased levels of p-p38MAPK, p-ERK and p-JNK, which are known to be activated in microglia (p-p38MAPK and p-ERK) and astrocyte (p-JNK). Experiments using primary cell cultures also revealed that the JAK2/STAT3 pathway promoted microglia and astrocyte activation after lipopolysaccharide stimulation. Furthermore, JAK2/STAT3 signaling and pain behaviors were significantly attenuated when the rats were treated with anti-IL-6 antibody. Finally, minocycline, a tetracycline antibiotic, inhibited IL-6/JAK2/STAT3 signaling pathway in activated glial cells and restored nociceptive thresholds and the hyperresponsiveness of dorsal neurons. These results suggest an important role of the IL-6/JAK2/STAT3 pathway in the activation of microglia and astrocytes and in the maintenance of chronic below-level pain after SCI.
脊髓损伤（SCI）后，控制胶质细胞（如小胶质细胞和星形胶质细胞）的激活已成为治疗神经病理性疼痛的一种有前途的策略。然而，SCI 后神经病理性疼痛发展和维持过程中胶质细胞激活涉及的信号机制尚未得到充分阐明。在这项研究中，我们研究了 JAK2/STAT3 通路与 SCI 后慢性神经病理性疼痛发展和维持过程中胶质细胞激活相关的潜在作用和机制。在挫伤性 SCI 后 1 个月，JAK2/STAT3 通路在伤害感受处理区域的腰椎脊髓中的小胶质细胞和星形胶质细胞中明显上调。此外，JAK2 抑制剂 AG490 显著抑制机械性痛觉过敏和热痛觉过敏。特别是，AG490 处理抑制了腰椎（L）4-5 背角中的小胶质细胞和星形胶质细胞的激活，并显著降低了已知在小胶质细胞（p-p38MAPK 和 p-ERK）和星形胶质细胞（p-JNK）中激活的 p-p38MAPK、p-ERK 和 p-JNK 的水平。使用原代细胞培养物进行的实验还表明，JAK2/STAT3 通路在脂多糖刺激后促进小胶质细胞和星形胶质细胞的激活。此外，当用抗 IL-6 抗体治疗大鼠时，JAK2/STAT3 信号转导和疼痛行为明显减弱。最后，米诺环素是一种四环素抗生素，可抑制活化胶质细胞中的 IL-6/JAK2/STAT3 信号通路，恢复伤害感受阈值和背神经元的高反应性。这些结果表明，IL-6/JAK2/STAT3 通路在 SCI 后小胶质细胞和星形胶质细胞的激活以及慢性下位疼痛的维持中起重要作用。
