mir-500-Mediated GAD67 Downregulation Contributes to Neuropathic Pain
mir-500-Mediated GAD67 Downregulation Contributes to Neuropathic Pain
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mir-500 介导的 GAD67 下调导致神经性疼痛
DOI：
10.1523/jneurosci.0646-16.2016
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发表时间：
2016-06-08
影响因子：
5.3
通讯作者：
Xin, Wen-Jun
中科院分区：
文献类型：
--
作者：
Huang, Zhen-Zhen;Wei, Jia-You;Xin, Wen-Jun
神经病理性疼痛是一种常见的神经生物学疾病，涉及从基因调节到突触功能障碍的多方面适应不良，但突触功能障碍与持续性疼痛相关基因之间的相互作用仍然难以捉摸。在本研究中，我们发现由化疗药物紫杉醇或L5前根切断诱导的神经病理性疼痛通过减少GAD 67表达而显著损害脊髓背角神经元的GABA能突触的功能。我们还发现mir-500的表达显著增加，并通过靶向Gad 1基因在背角的特定位点参与GAD 67表达的调节。此外，敲除mir-500或使用mir-500 Escheromir可以挽救脊髓背角神经元中的GABA能突触，并减轻神经病理性疼痛大鼠的致敏疼痛行为。据我们所知，这是第一个研究mir-500在神经病理性疼痛过程中的功能意义和潜在的分子机制，这为神经病理性疼痛的新治疗方案的开发提供了线索。神经病理性疼痛是一种常见的神经生物学疾病，涉及从基因调节到突触功能障碍的多方面适应不良，但其潜在的分子机制仍然难以捉摸。本研究首次阐明了mir-500介导的脊髓GABA能功能障碍和致敏疼痛行为的机制，该机制在由化疗药物紫杉醇或L5腹根横断诱导的神经性疼痛中起作用，这为神经性疼痛的新治疗选择的发展提供了线索。
Neuropathic pain is a common neurobiological disease involving multifaceted maladaptations ranging from gene modulation to synaptic dysfunction, but the interactions between synaptic dysfunction and the genes that are involved in persistent pain remain elusive. In the present study, we found that neuropathic pain induced by the chemotherapeutic drug paclitaxel or L5 ventral root transection significantly impaired the function of GABAergic synapses of spinal dorsal horn neurons via the reduction of the GAD67 expression. We also found that mir-500 expression was significantly increased and involved in the modulation of GAD67 expression via targeting the specific site of Gad1 gene in the dorsal horn. In addition, knock-out of mir-500 or using mir-500 antagomir rescued the GABAergic synapses in the spinal dorsal horn neurons and attenuated the sensitized pain behavior in the rats with neuropathic pain. To our knowledge, this is the first study to investigate the function significance and the underlying molecular mechanisms of mir-500 in the process of neuropathic pain, which sheds light on the development of novel therapeutic options for neuropathic pain. SIGNIFICANCE STATEMENT Neuropathic pain is a common neurobiological disease involving multifaceted maladaptations ranging from gene modulation to synaptic dysfunction, but the underlying molecular mechanisms remain elusive. The present study illustrates for the first time a mir-500-mediated mechanism underlying spinal GABAergic dysfunction and sensitized pain behavior in neuropathic pain induced by the chemotherapeutic drug paclitaxel or L5 ventral root transection, which sheds light on the development of novel therapeutic options for neuropathic pain.