School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, 75080, USA.
Department of Bioengineering, University of Texas at Dallas, Richardson, TX, 75080, USA.
Neuropsychopharmacology. 2020 Feb;45(3):524-533. doi: 10.1038/s41386-019-0537-y. Epub 2019 Oct 7.
Neuropathic pain caused by nerve injury presents with severe spontaneous pain and a variety of comorbidities, including deficits in higher executive functions. None of these clinical problems are adequately treated with current analgesics. Targeting of the mitogen-activated protein kinase-interacting kinase (MNK1/2) and its phosphorylation target, the mRNA cap binding protein eIF4E, attenuates many types of nociceptive plasticity induced by inflammatory mediators and chemotherapeutic drugs but inhibiting this pathway does not alter nerve injury-induced mechanical allodynia. We used genetic manipulations and pharmacology to inhibit MNK-eIF4E activity in animals with spared nerve injury, a model of peripheral nerve injury (PNI)-induced neuropathic pain. We assessed the presence of spontaneous pain using conditioned place preference. We also tested performance in a medial prefrontal cortex (mPFC)-dependent rule-shifting task. WT neuropathic animals showed signs of spontaneous pain and were significantly impaired in the rule-shifting task while genetic and pharmacological inhibition of the MNK-eIF4E signaling axis protected against and reversed spontaneous pain and PNI-mediated cognitive impairment. Additionally, pharmacological and genetic inhibition of MNK-eIF4E signaling completely blocked and reversed maladaptive shortening in the length of axon initial segments (AIS) in the mPFC of PNI mice. Surprisingly, these striking positive outcomes on neuropathic pain occurred in the absence of any effect on mechanical allodynia, a standard test for neuropathic pain efficacy. Our results illustrate new testing paradigms for determining preclinical neuropathic pain efficacy and point to the MNK inhibitor tomivosertib (eFT508) as an important drug candidate for neuropathic pain treatment.
神经损伤引起的神经性疼痛表现为严重的自发性疼痛和多种合并症，包括高级执行功能缺陷。目前的镇痛剂无法有效治疗这些临床问题。靶向丝裂原活化蛋白激酶相互作用激酶（MNK1/2）及其磷酸化靶标，mRNA 帽结合蛋白 eIF4E，可以减轻炎症介质和化疗药物引起的多种伤害性可塑性，但抑制该途径不会改变神经损伤引起的机械性痛觉过敏。我们使用遗传操作和药理学方法，在 spared nerve injury（一种周围神经损伤（PNI）诱导的神经性疼痛模型）动物中抑制 MNK-eIF4E 活性。我们使用条件性位置偏爱来评估自发性疼痛的存在。我们还测试了内侧前额叶皮层（mPFC）依赖性规则转换任务的表现。WT 神经性动物表现出自发性疼痛的迹象，并且在规则转换任务中明显受损，而 MNK-eIF4E 信号通路的遗传和药理学抑制可预防和逆转自发性疼痛和 PNI 介导的认知障碍。此外，MNK-eIF4E 信号的药理学和遗传学抑制完全阻断并逆转了 PNI 小鼠 mPFC 中轴突起始段（AIS）长度的适应性缩短。令人惊讶的是，这些对神经性疼痛的显著积极结果是在对机械性痛觉过敏（神经性疼痛疗效的标准测试）没有任何影响的情况下发生的。我们的结果说明了用于确定临床前神经性疼痛疗效的新测试范例，并指出 MNK 抑制剂 tomivosertib（eFT508）是神经性疼痛治疗的重要候选药物。
