Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.

中文翻译：

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Tomivosertib 减少神经根病患者背根神经节神经元的异位活性


背根神经节 （DRG） 神经元的自发活动是患有这种基本上未经治疗的疾病的患者神经性疼痛的关键驱动因素。虽然在驱动自发活动的临床前模型中已经检查了许多细胞内信号机制，但没有一个直接在自发活跃的人类伤害感受器上进行测试。使用在胸椎切除术中恢复的培养的 DRG 神经元，我们表明丝裂原活化蛋白激酶相互作用激酶 （MNK） 与 tomivosertib （eFT508， 25 nM） 的抑制可逆地抑制人类感觉神经元的自发活动，这些神经元可能是伤害感受器基于大小和与疼痛皮节相关的动作电位特征在治疗后几分钟内。Tomivosertib 治疗还降低了动作电位振幅并产生了超极化电流后幅度的变化，表明药物治疗改变了 Na + 和 K + 通道活性。与对电生理学的影响平行，eFT508 处理导致原代感觉神经元（MNK 的特异性底物）中 eIF4E 丝氨酸 209 磷酸化在药物治疗后 2 分钟内严重丢失。我们的结果为未来在神经性疼痛临床试验中测试 MNK 抑制剂创造了令人信服的案例。