Browsing by Author "Moy, Jamie K."
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Item A Critical Role for Dopamine D5 Receptors in Pain Chronicity in Male Mice(Soc Neuroscience) Megat, Salim; Shiers, Stephanie; Moy, Jamie K.; Barragán-Iglesias, Paulino; Pradhan, Grishma; Megat, Salim; Dussor, Gregory; Price, Theodore J.; 0000-0003-2186-6770 (Megat, S); 0000-0002-9646-1850 (Shiers, S); 0000-0001-8579-5540 (Moy, JK); 0000-0003-3178-8606 (Barragán-Iglesias, P); 0000-0002-6971-6221 (Price, TJ); Megat, Salim; Shiers, Stephanie; Moy, Jamie K.; Barragan-Iglesias, Paulino; Pradhan, Grishma; Seal, Rebecca P.; Dussor, Gregory; Price, Theodore J.Dopaminergic modulation of spinal cord plasticity has long been recognized, but circuits affected by this system and the precise receptor subtypes involved in this modulation have not been defined. Dopaminergic modulation from the A11 nucleus of the hypothalamus contributes to plasticity in a model of chronic pain called hyperalgesic priming. Here we tested the hypothesis that the key receptor subtype mediating this effect is the D5 receptor (D5R). We find that a spinally directed lesion of dopaminergic neurons reverses hyperalgesic priming in both sexes and that a D1/D5 antagonist transiently inhibits neuropathic pain. We used mice lacking D5Rs (DRD5KO mice) to show that carrageenan, interleukin 6, as well as BDNF-induced hyperalgesia and priming are reduced specifically in male mice. These male DRD5KO mice also show reduced formalin pain responses and decreased heat pain. To characterize the subtypes of dorsal horn neurons engaged by dopamine signaling in the hyperalgesic priming model, we used c-fos labeling. We find that a mixed D1/D5 agonist given spinally to primed mice activates a subset of neurons in lamina III and IV of the dorsal horn that coexpress PAX2, a transcription factor for GABAergic interneurons. In line with this, we show that gabazine, a GABA-A receptor antagonist, is antihyperalgesic in primed mice exposed to spinal administration of a D1/D5 agonist. Therefore, the D5R, in males, and the D1R, in females, exert a powerful influence over spinal cord circuitry in pathological pain likely via modulation of deep dorsal horn GABAergic neurons.Item eIF4E Phosphorylation Influences BDNF mRNA Translation in Mouse Dorsal Root Ganglion Neurons(Frontiers Media SA) Moy, Jamie K.; Khoutorsky, Arkady; Asiedu, Marina N.; Dussor, Gregory; Price, Theodore J.; 0000-0002-6971-6221 (Price, TJ); Moy, Jamie K.; Asiedu, Marina N.; Dussor, Gregory; Price, Theodore J.Plasticity in dorsal root ganglion (DRG) neurons that promotes pain requires activity-dependent mRNA translation. Protein synthesis inhibitors block the ability of many pain-promoting molecules to enhance excitability in DRG neurons and attenuate behavioral signs of pain plasticity. In line with this, we have recently shown that phosphorylation of the 5' cap-binding protein, eIF4E, plays a pivotal role in plasticity of DRG nociceptors in models of hyperalgesic priming. However, mRNA targets of eIF4E phosphorylation have not been elucidated in the DRG. Brain-derived neurotrophic factor (BDNF) signaling from nociceptors in the DRG to spinal dorsal horn neurons is an important mediator of hyperalgesic priming. Regulatory mechanisms that promote pain plasticity via controlling BDNF expression that is involved in promoting pain plasticity have not been identified. We show that phosphorylation of eIF4E is paramount for BDNF mRNA translation in the DRG. BDNF mRNA translation is reduced in mice lacking eIF4E phosphorylation (eIF4E^(S209A)) and pro-nociceptive factors fail to increase BDNF protein levels in the DRGs of these mice despite robust upregulation of BDNF-201 mRNA levels. Importantly, bypassing the DRG by giving intrathecal injection of BDNF in eIF4E^(S209A) mice creates a strong hyperalgesic priming response that is normally absent or reduced in these mice. We conclude that eIF4E phosphorylation-mediated translational control of BDNF expression is a key mechanism for nociceptor plasticity leading to hyperalgesic priming.Item The MNK–eIF4E Signaling Axis Contributes to Injury-Induced Nociceptive Plasticity and the Development of Chronic Pain(Society for Neuroscience) Moy, Jamie K.; Khoutorsky, A.; Black, Brian J.; Kuhn, Jasper L.; Barragán-Iglesias, Paulino; Megat, Salim; Burton, Michael D.; Burgos-Vega, Carolina C.; Melemedjian, O. K.; Boitano, S.; Vagner, J.; Gkogkas, C. G.; Pancrazio, Joseph J.; Mogil, J. S.; Dussor, Gregory; Sonenberg, N.; Price, Theodore J.; 0000 0001 3721 4764 (Dussor, G); 0000-0001-8579-5540 (Moy, JK); 0000-0001-8571-6486 (Black, B); 0000-0001-6524-9411 (Kuhn JL); 0000-0003-3178-8606 (Barragán-Iglesias, P); 0000-0002-6971-6221 (Price, TJ); Moy, Jamie K.; Asiedu, Marina N.; Black, Brian J.; Kuhn, Jasper L.; Barragán-Iglesias, Paulino; Megat, Salim; Burton, Michael D.; Burgos-Vega, Carolina C.; Pancrazio, Joseph J.; Dussor, Gregory; Price, Theodore J.Injury-induced sensitization of nociceptors contributes to pain states and the development of chronic pain. Inhibiting activity-dependent mRNA translation through mechanistic target of rapamycin and mitogen-activated protein kinase (MAPK) pathways blocks the development of nociceptor sensitization. These pathways convergently signal to the eukaryotic translation initiation factor (eIF) 4F complex to regulate the sensitization of nociceptors, but the details of this process are ill defined. Here we investigated the hypothesis that phosphorylation of the 5β cap-binding protein eIF4E by its specific kinase MAPK interacting kinases (MNKs) 1/2 is a key factor in nociceptor sensitization and the development of chronic pain. Phosphorylation of ser209 on eIF4E regulates the translation of a subset of mRNAs. We show that pronociceptive and inflammatory factors, such as nerve growth factor (NGF), interleukin-6 (IL-6), and carrageenan, produce decreased mechanical and thermal hypersensitivity, decreased affective pain behaviors, and strongly reduced hyperalgesic priming in mice lacking eIF4E phosphorylation (eIF4ES209A). Tests were done in both sexes, and no sex differences were found. Moreover, in patch-clamp electrophysiology and Ca2+ imaging experiments on dorsal root ganglion neurons, NGF- and IL-6-induced increases in excitability were attenuated in neurons from eIF4ES209A mice. These effects were recapitulated in Mnk1/2-/- mice and with the MNK1/2 inhibitor cercosporamide. We also find that cold hypersensitivity induced by peripheral nerve injury is reduced in eIF4ES209A and Mnk1/2-/- mice and following cercosporamide treatment. Our findings demonstrate that the MNK1/2–eIF4E signaling axis is an important contributing factor to mechanisms of nociceptor plasticity and the development of chronic pain.Item Nociceptor Translational Profiling Reveals the Ragulator-Rag GTPase Complex as a Critical Generator of Neuropathic Pain(Soc Neuroscience, 2019-01-16) Megat, Salim; Ray, Pradipta R.; Moy, Jamie K.; Lou, Tzu-Fang; Barragan-Iglesias, Paulino; Li, Yan; Pradhan, Grishma; Wanghzou, Andi; Ahmad, Ayesha; Burton, Michael D.; North, Robert Y.; Dougherty, Patrick M.; Khoutorsky, Arkady; Sonenberg, Nahum; Webster, Nevin R.; Dussor, Gregory; Campbell, Zachary T.; Price, Theodore J.; 0000-0003-4281-3985 (Pradhan, G); 0000-0002-0628-824X (Burton, MD); 0000-0002-3768-6996 (Campbell, ZT); 0000-0002-6971-6221 (Price, TJ); Megat, Salim; Ray, Pradipta R.; Moy, Jamie K.; Lou, Tzu-Fang; Barragan-Iglesias, Paulino; Pradhan, Grishma; Wanghzou, Andi; Ahmad, Ayesha; Burton, Michael D.; Dussor, Gregory; Campbell, Zachary T.; Price, Theodore J.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 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 mTORC1 activation driven by MNK1-eIF4E signaling. RagA, aGTPase 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.Item Translation Regulation in Central and Peripheral Pain Plasticity(2017-05) Moy, Jamie K.; Price, Theodore J.Pain under normal circumstances serves as a protective mechanism allowing recovery and survival. However, when pain becomes chronic, it no longer provides preservation but rather debilitation. Chronic pain is an important medical problem affecting greater than 33% of the population in America and current treatment options are only effective in a small percentage of the population and often accompanied with side effects. Determining the underlying molecular mechanisms of the maintenance and transition to chronic pain would lead us to developing new therapeutic treatments. Many studies suggest that translational control of gene expression is a key process for the regulation of plasticity in the nervous system. Multiple lines of evidence indicate that translation control plays a critical role in pathological pain plasticity, but precise gene targets have thus far not been elucidated. Brain-derived neurotrophic factor (BDNF) signaling through its cognate receptor, TrkB, is a well-known promoter of synaptic plasticity at nociceptive synapses in the dorsal horn of the spinal cord. However, the downstream effects contributing to the maintenance of a chronic pain state remain elusive. The goal of our research is to further understand the biochemical mechanisms driving chronic pain using pharmacological techniques and transgenic mice. Our work provides novel insight into mechanisms driving pain chronification and defines MNK regulation of eIF4E phosphorylation as a key target for pain therapeutics.