Li Yan, Uhelski Megan L, North Robert Y, Mwirigi Juliet M, Tatsui Claudio E, Cata Juan P, Corrales German, Price Theodore J, Dougherty Patrick M
Department of Anesthesia and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA, 77030.
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA, 77030.
bioRxiv. 2023 Jun 14:2023.06.13.544811. doi: 10.1101/2023.06.13.544811.
Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in preclinical models and in patients suffering from this largely untreated disease. While many intracellular signaling mechanisms have been examined in preclinical models that drive this spontaneous activity (SA), none of these have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we show that inhibition of mitogen activated protein kinase interacting kinase (MNK) with eFT508 (25 nM) reverses SA in human sensory neurons associated with painful dermatomes. MNK inhibition in spontaneously active nociceptors decreased action potential amplitude and produced alterations in the magnitude of afterhyperpolarizing currents suggesting modification of Na and K channel activity downstream of MNK inhibition. The effects of MNK inhibition on SA took minutes to emerge and were reversible over time with eFT508 washout. MNK inhibition with eFT508 led to a profound loss of eIF4E Serine 209 phosphorylation, a specific target of the kinase, within 2 min of drug treatment, consistent with the rapid action of the drug on SA in electrophysiology experiments. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.
背根神经节（DRG）神经元的自发活动是临床前模型以及患有这种大多未得到治疗疾病的患者中神经性疼痛的关键驱动因素。虽然在驱动这种自发活动（SA）的临床前模型中已经研究了许多细胞内信号传导机制，但这些机制均未在自发活动的人类伤害感受器上直接进行测试。利用在胸椎切除术期间回收的培养DRG神经元，我们发现用eFT508（25 nM）抑制丝裂原活化蛋白激酶相互作用激酶（MNK）可逆转与疼痛皮节相关的人类感觉神经元中的SA。对自发活动的伤害感受器进行MNK抑制可降低动作电位幅度，并使超极化后电流的大小发生改变，这表明MNK抑制下游的钠和钾通道活性发生了改变。MNK抑制对SA的影响需要几分钟才能显现，并且随着时间的推移，通过洗脱eFT508是可逆的。在药物治疗后2分钟内，用eFT508抑制MNK导致激酶的特异性靶点eIF4E丝氨酸209磷酸化显著丧失，这与该药物在电生理实验中对SA的快速作用一致。我们的结果为未来在神经性疼痛的临床试验中测试MNK抑制剂提供了令人信服的依据。
