Excess intracellular ATP causes neuropathic pain following spinal cord injury
Excess intracellular ATP causes neuropathic pain following spinal cord injury
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DOI：
10.1007/s00018-022-04510-z
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发表时间：
2022-08
影响因子：
8
通讯作者：
N. Nakajima;Yu-ichirou Ohnishi;M. Yamamoto;Daiki Setoyama;H. Imai;T. Takenaka;Mari Matsumoto;
中科院分区：
文献类型：
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作者：
N. Nakajima;Yu-ichirou Ohnishi;M. Yamamoto;Daiki Setoyama;H. Imai;T. Takenaka;Mari Matsumoto;
脊髓损伤（NP-SCI）后的顽固性神经性疼痛降低了患者的生活质量。ATP过度释放到细胞外间隙通过嘌呤能受体引起神经炎症。神经炎症在NP的发生和维持中起着重要作用。然而，很少有人知道是否细胞外ATP引起NP-SCI。我们发现，在本研究中，在病变部位的细胞内ATP过量引起的水平NP-SCI。在水平异常性疼痛阴性和阳性组中，体重、运动功能或运动行为无显著差异。异常性疼痛阳性小鼠损伤部位的细胞内ATP水平显著高于异常性疼痛阴性小鼠。代谢组学分析显示，异常性疼痛阴性和异常性疼痛阳性小鼠之间的ATP产生或降解没有显著差异。发现异常性疼痛小鼠的背角神经元在静息状态下失活，这表明由于神经不活动导致ATP消耗减少导致细胞内ATP积聚。与静息状态下的结果相反，机械刺激增加背角神经活动和损伤部位细胞外ATP释放。在非异常性疼痛小鼠的损伤部位强制产生细胞内ATP诱导异常性疼痛。在异常性疼痛小鼠中抑制P2 X4受体可减轻异常性疼痛。这些结果表明，在静息状态下，细胞内ATP的过量积累导致在水平的NP-SCI，作为机械刺激下ATP的细胞外释放的结果。
Intractable neuropathic pain following spinal cord injury (NP-SCI) reduces a patient’s quality of life. Excessive release of ATP into the extracellular space evokes neuroinflammation via purinergic receptor. Neuroinflammation plays an important role in the initiation and maintenance of NP. However, little is known about whether or not extracellular ATP cause NP-SCI. We found in the present study that excess of intracellular ATP at the lesion site evokes at-level NP-SCI. No significant differences in the body weight, locomotor function, or motor behaviors were found in groups that were negative and positive for at-level allodynia. The intracellular ATP level at the lesion site was significantly higher in the allodynia-positive mice than in the allodynia-negative mice. A metabolome analysis revealed that there were no significant differences in the ATP production or degradation between allodynia-negative and allodynia-positive mice. Dorsal horn neurons in allodynia mice were found to be inactivated in the resting state, suggesting that decreased ATP consumption due to neural inactivity leads to a build-up of intracellular ATP. In contrast to the findings in the resting state, mechanical stimulation increased the neural activity of dorsal horn and extracellular ATP release at lesion site. The forced production of intracellular ATP at the lesion site in non-allodynia mice induced allodynia. The inhibition of P2X4 receptors in allodynia mice reduced allodynia. These results suggest that an excess buildup of intracellular ATP in the resting state causes at-level NP-SCI as a result of the extracellular release of ATP with mechanical stimulation.