University of Texas at Dallas, School of Behavioral and Brain Sciences, 800 Campbell Rd, Richardson, Texas, 75080.
University of Texas at Dallas, Center for Advanced Pain Studies, 800 Campbell Rd, Richardson, Texas, 75080.
J Neurosci. 2019 Jan 16;39(3):393-411. doi: 10.1523/JNEUROSCI.2661-18.2018. Epub 2018 Nov 20.
Nociceptors, sensory neurons in the DRG that detect damaging or potentially damaging stimuli, are key drivers of neuropathic pain. Injury to these neurons causes activation of translation regulation signaling, including the mechanistic target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase interacting kinase (MNK) eukaryotic initiation factor (eIF) 4E pathways. This is a mechanism driving changes in excitability of nociceptors that is critical for the generation of chronic pain states; however, the mRNAs that are translated to lead to this plasticity have not been elucidated. To address this gap in knowledge, we used translating ribosome affinity purification in male and female mice to comprehensively characterize mRNA translation in -positive nociceptors in chemotherapy-induced neuropathic pain (CIPN) caused by paclitaxel treatment. This unbiased method creates a new resource for the field, confirms many findings in the CIPN literature and also find extensive evidence for new target mechanisms that may cause CIPN. We provide evidence that an underlying mechanism of CIPN is sustained mTORC1 activation driven by MNK1-eIF4E signaling. RagA, a GTPase controlling mTORC1 activity, is identified as a novel target of MNK1-eIF4E signaling. This demonstrates a novel translation regulation signaling circuit wherein MNK1-eIF4E activity drives mTORC1 via control of RagA translation. CIPN and RagA translation are strongly attenuated by genetic ablation of eIF4E phosphorylation, MNK1 elimination or treatment with the MNK inhibitor eFT508. We identify a novel translational circuit for the genesis of neuropathic pain caused by chemotherapy with important implications for therapeutics. Neuropathic pain affects up to 10% of the population, but its underlying mechanisms are incompletely understood, leading to poor treatment outcomes. We used translating ribosome affinity purification technology to create a comprehensive translational profile of DRG nociceptors in naive mice and at the peak of neuropathic pain induced by paclitaxel treatment. We reveal new insight into how mechanistic target of rapamycin complex 1 is activated in neuropathic pain pointing to a key role of MNK1-eIF4E-mediated translation of a complex of mRNAs that control mechanistic target of rapamycin complex 1 signaling at the surface of the lysosome. We validate this finding using genetic and pharmacological techniques. Our work strongly suggests that MNK1-eIF4E signaling drives CIPN and that a drug in human clinical trials, eFT508, may be a new therapeutic for neuropathic pain.
伤害感受器是检测有害或潜在有害刺激的 DRG 中的感觉神经元，是神经病理性疼痛的关键驱动因素。这些神经元的损伤会导致翻译调节信号的激活，包括雷帕霉素复合物 1（mTORC1）和丝裂原激活蛋白激酶相互作用激酶（MNK）真核起始因子（eIF）4E 途径。这是驱动伤害感受器兴奋性变化的一种机制，对于慢性疼痛状态的产生至关重要；然而，导致这种可塑性的翻译 mRNA 尚未阐明。为了弥补这一知识空白，我们使用翻译核糖体亲和纯化技术，在紫杉醇治疗引起的化疗诱导性神经病理性疼痛（CIPN）的雄性和雌性小鼠中，全面描述了 -阳性伤害感受器中的 mRNA 翻译。这种无偏方法为该领域创造了新的资源，证实了 CIPN 文献中的许多发现，还为可能导致 CIPN 的新靶机制提供了广泛的证据。我们提供的证据表明，CIPN 的一个潜在机制是 MNK1-eIF4E 信号驱动的持续 mTORC1 激活。RagA，一种控制 mTORC1 活性的 GTPase，被确定为 MNK1-eIF4E 信号的新靶标。这证明了一个新的翻译调节信号通路，其中 MNK1-eIF4E 活性通过控制 RagA 翻译来驱动 mTORC1。通过基因敲除 eIF4E 磷酸化、消除 MNK1 或用 MNK 抑制剂 eFT508 治疗，CIPN 和 RagA 翻译都被强烈抑制。我们确定了一种新的化疗引起的神经病理性疼痛的翻译电路，这对治疗具有重要意义。神经病理性疼痛影响了多达 10%的人群，但其潜在机制尚不完全清楚，导致治疗效果不佳。我们使用翻译核糖体亲和纯化技术，在紫杉醇治疗引起的神经病理性疼痛高峰时，为幼稚小鼠和 DRG 伤害感受器创建了一个全面的翻译图谱。我们揭示了机械靶标复合物 1 在神经病理性疼痛中被激活的新见解，指出 MNK1-eIF4E 介导的翻译复合物在溶酶体表面控制机械靶标复合物 1 信号的一组 mRNAs 的翻译在机械靶标复合物 1 的激活中起着关键作用。我们使用遗传和药理学技术验证了这一发现。我们的工作强烈表明，MNK1-eIF4E 信号驱动 CIPN，并且一种在人类临床试验中使用的药物，eFT508，可能是一种治疗神经病理性疼痛的新疗法。
