PT  - JOURNAL ARTICLE
AU  - Salim Megat
AU  - Pradipta R. Ray
AU  - Jamie K. Moy
AU  - Tzu-Fang Lou
AU  - Paulino Barragan-Iglesias
AU  - Yan Li
AU  - Grishma Pradhan
AU  - Andi Wangzhou
AU  - Ayesha Ahmad
AU  - Robert Y. North
AU  - Patrick M. Dougherty
AU  - Arkady Khoutorsky
AU  - Nahum Sonenberg
AU  - Kevin R. Webster
AU  - Gregory Dussor
AU  - Zachary T. Campbell
AU  - Theodore J. Price
TI  - Nociceptor translational profiling reveals the RagA-mTORC1 network as a critical generator of neuropathic pain
AID  - 10.1101/336784
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 336784
4099  - http://biorxiv.org/content/early/2018/06/02/336784.short
4100  - http://biorxiv.org/content/early/2018/06/02/336784.full
AB  - Pain sensing neurons, nociceptors, are key drivers of neuropathic pain. We used translating ribosome affinity purification (TRAP) to comprehensively characterize up-and down-regulated mRNA translation in Scn10a-positive nociceptors in chemotherapy-induced neuropathic pain. We provide evidence that an underlying mechanism driving these changes in gene expression is a sustained mTORC1 activation driven by MNK1-eIF4E signaling. RagA, a GTPase controlling mTORC1 activity, is identified as a novel target of MNK1-eIF4E signaling, demonstrating a new link between these distinct signaling pathways. Neuropathic pain and RagA translation are strongly attenuated by genetic ablation of eIF4E phosphorylation, MNK1 elimination or treatment with the MNK inhibitor eFT508. We reveal a novel translational circuit for the genesis of neuropathic pain with important implications for next generation neuropathic pain therapeutics.One Sentence Summary Cell-specific sequencing of translating mRNAs elucidates signaling pathology that can be targeted to reverse neuropathic pain