JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats
JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats
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DOI：
10.1093/brain/awr025
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发表时间：
2011-04-01
期刊：
影响因子：
14.5
通讯作者：
Inoue, Kazuhide
中科院分区：
文献类型：
--
作者：
Tsuda, Makoto;Kohro, Yuta;Inoue, Kazuhide
神经性疼痛是一种使人衰弱的疼痛状况，是神经系统损伤的常见后果。神经性疼痛的最佳治疗是一个主要的临床挑战，因为潜在的机制仍然不清楚，目前可用的治疗方法往往是无效的。新出现的证据表明，周围神经损伤将静息的脊髓胶质细胞转化为神经病理性疼痛的发展和维持所需的反应性细胞。然而，神经损伤后反应性星形胶质细胞增生的机制在很大程度上是未知的。在本研究中，我们研究了细胞增殖，反应性星形胶质细胞增生的一个关键过程，并确定了脊髓神经损伤，一个众所周知的模型，神经病理性疼痛的大鼠背角星形胶质细胞的暂时限制增殖。我们发现神经损伤诱导的星形胶质细胞增殖需要Janus激酶信号转导和转录激活因子3信号通路。神经损伤诱导背角星形胶质细胞发生显著的信号转导子和转录激活子3核转位，这是信号转导子和转录激活子3激活的主要指标。对神经损伤大鼠鞘内注射Janus激酶-信号转导子和转录激活子3信号转导抑制剂，可减少背角星形胶质细胞的增殖数量，并可从已建立的触觉异常性疼痛中恢复，触觉异常性疼痛是神经性疼痛的主要症状，其特征在于由无害刺激引起的疼痛超敏反应。此外，恢复触觉异常性疼痛也产生了直接抑制星形胶质细胞分裂的神经损伤大鼠鞘内给药的细胞周期抑制剂flavopiridol。总之，这些结果意味着Janus激酶信号转导子和转录激活子3信号通路是星形胶质细胞增殖和维持触觉异常性疼痛的关键转导子，并且可能是神经病理性疼痛的治疗靶点。
Neuropathic pain, a debilitating pain condition, is a common consequence of damage to the nervous system. Optimal treatment of neuropathic pain is a major clinical challenge because the underlying mechanisms remain unclear and currently available treatments are frequently ineffective. Emerging lines of evidence indicate that peripheral nerve injury converts resting spinal cord glia into reactive cells that are required for the development and maintenance of neuropathic pain. However, the mechanisms underlying reactive astrogliosis after nerve injury are largely unknown. In the present study, we investigated cell proliferation, a critical process in reactive astrogliosis, and determined the temporally restricted proliferation of dorsal horn astrocytes in rats with spinal nerve injury, a well-known model of neuropathic pain. We found that nerve injury-induced astrocyte proliferation requires the Janus kinase-signal transducers and activators of transcription 3 signalling pathway. Nerve injury induced a marked signal transducers and activators of transcription 3 nuclear translocation, a primary index of signal transducers and activators of transcription 3 activation, in dorsal horn astrocytes. Intrathecally administering inhibitors of Janus kinase-signal transducers and activators of transcription 3 signalling to rats with nerve injury reduced the number of proliferating dorsal horn astrocytes and produced a recovery from established tactile allodynia, a cardinal symptom of neuropathic pain that is characterized by pain hypersensitivity evoked by innocuous stimuli. Moreover, recovery from tactile allodynia was also produced by direct suppression of dividing astrocytes by intrathecal administration of the cell cycle inhibitor flavopiridol to nerve-injured rats. Together, these results imply that the Janus kinase-signal transducers and activators of transcription 3 signalling pathway are critical transducers of astrocyte proliferation and maintenance of tactile allodynia and may be a therapeutic target for neuropathic pain.