Foxo1 selectively regulates static mechanical pain by interacting with Nav1.7.
Foxo1 selectively regulates static mechanical pain by interacting with Nav1.7.
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DOI：
10.1097/j.pain.0000000000002055
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发表时间：
2020-08
期刊：
影响因子：
7.4
通讯作者：
Xiaolin Zhang;R. Lai;Zi-Hang Chen;Xiongxiong Zhong;Xian-Ying Cao;Xi Zhang;Yi-bin Xiao;Jun-Chao Wan
中科院分区：
文献类型：
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作者：
Xiaolin Zhang;R. Lai;Zi-Hang Chen;Xiongxiong Zhong;Xian-Ying Cao;Xi Zhang;Yi-bin Xiao;Jun-Chao Wan
机械性异常性疼痛是数百万慢性疼痛患者的一种使人衰弱的病症。机械性异常性疼痛可以表现为不同的形式，包括刷诱发的动态异常性疼痛和被动诱发的静态异常性疼痛。在神经系统中，叉头蛋白Foxo 1在神经元结构和功能中起着关键作用。然而，Foxo 1在躯体感觉信号中的作用仍不清楚。在这里，我们发现Foxo 1选择性地调节静态机械疼痛。Foxo 1敲低降低了正常大鼠对静态机械刺激的敏感性，并减弱了神经性、炎症性和化疗疼痛大鼠模型的静态机械性异常性疼痛。相反，Foxo 1过表达选择性地增强对静态机械刺激的敏感性，并引起静态机械异常性疼痛。此外，Foxo 1与电压门控钠Nav1.7通道相互作用，并通过加速激活而不是通过改变背根神经节神经元中Nav1.7的表达来增加Nav1.7电流密度。此外，发现慢性疼痛患者血清Foxo 1水平升高，并与慢性疼痛的严重程度呈正相关。因此，血清Foxo 1水平可作为慢性疼痛的生物学指标，用于慢性疼痛的预测和诊断。此外，选择性阻断Foxo 1/Nav1.7相互作用可能为机械性疼痛患者提供新的治疗方法。
Mechanical allodynia is a debilitating condition for millions of patients with chronic pain. Mechanical allodynia can manifest in distinct forms, including brush-evoked dynamic and filament-evoked static allodynia. In the nervous system, the forkhead protein Foxo1 plays a critical role in neuronal structures and functions. However, the role of Foxo1 in the somatosensory signal remains unclear. Here, we found that Foxo1 selectively regulated static mechanical pain. Foxo1 knockdown decreased sensitivity to static mechanical stimuli in normal rats and attenuated static mechanical allodynia in rat models for neuropathic, inflammatory, and chemotherapy pain. Conversely, Foxo1 overexpression selectively enhanced sensitivity to static mechanical stimuli and provoked static mechanical allodynia. Furthermore, Foxo1 interacted with voltage gated sodium Nav1.7 channels and increased the Nav1.7 current density by accelerating activation rather than by changing the expression of Nav1.7 in dorsal root ganglia neurons. In addition, the serum level of Foxo1 was found to be increased in chronic pain patients and to be positively correlated with the severity of chronic pain. Altogether, our findings suggest that serum Foxo1 level could be used as a biological marker for prediction and diagnosis of chronic pain. Moreover, selective blockade of Foxo1/Nav1.7 interaction may offer a new therapeutic approach in patients with mechanical pain.