Abstract
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 beenelucidated. To address this gapinknowledge, we usedtranslating ribosome affinity purificationinmale andfemale mice to comprehensively characterize mRNA translation in Scn10a-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 mTORC1activationdrivenbyMNK1-eIF4Esignaling. RagA, aGTPase controllingmTORC1activity, is identifiedas anovel 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.
Original language | English (US) |
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Pages (from-to) | 393-411 |
Number of pages | 19 |
Journal | Journal of Neuroscience |
Volume | 39 |
Issue number | 3 |
DOIs | |
State | Published - Jan 16 2019 |
Keywords
- Neuropathic pain
- Nociceptor
- TRAP
- eIF4E
- mTOR
ASJC Scopus subject areas
- General Neuroscience