Browsing by Author "Barragan-Iglesias, Paulino"
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Item Activation of the Integrated Stress Response in Nociceptors Drives Methylglyoxal-Induced Pain(Lippincott Williams & Wilkins, 2019-01) Barragan-Iglesias, Paulino; Kuhn, Jasper; Vidal-Cantu, Guadalupe C.; Belen Salinas-Abarca, Ana; Granados-Soto, Vinicio; Dussor, Gregory; Campbell, Zachary T.; Price, Theodore J.; 0000-0002-3768-6996 (Campbell, ZT); 0000-0002-6971-6221 (Price, TJ); Dussor, Gregory; Campbell, Zachary T.; Price, Theodore J.Methylglyoxal (MGO) is a reactive glycolytic metabolite associated with painful diabetic neuropathy at plasma concentrations between 500 nM and 5 μM. The mechanisms through which MGO causes neuropathic pain at these pathological concentrations are not known. Because MGO has been linked to diabetic neuropathic pain, which is prevalent and poorly treated, insight into this unsolved biomedical problem could lead to much needed therapeutics. Our experiments provide compelling evidence that ~ 1-μM concentrations of MGO activate the integrated stress response (ISR) in IB4-positive nociceptors in the dorsal root ganglion (DRG) of mice in vivo and in vitro. Blocking the integrated stress response with a specific inhibitor (ISRIB) strongly attenuates and reverses MGO-evoked pain. Moreover, ISRIB reduces neuropathic pain induced by diabetes in both mice and rats. Our work elucidates the mechanism of action of MGO in the production of pain at pathophysiologically relevant concentrations and suggests a new pharmacological avenue for the treatment of diabetic and other types of MGO-driven neuropathic pain.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 Inhibition of Poly(A)-Binding Protein with a Synthetic RNA Mimic Reduces Pain Sensitization in Mice(Nature Publishing Group, 2018-10-22) Barragan-Iglesias, Paulino; Lou, Tzu-Fang; Bhat, Vandita D.; Megat, Salim; Burton, Michael D.; Price, Theodore J.; Campbell, Zachary T.; 0000-0002-6971-6221 (Price, TJ); 0000-0002-3768-6996 (Campbell, ZT); Barragan-Iglesias, Paulino; Lou, Tzu-Fang; Bhat, Vandita D.; Megat, Salim; Burton, Michael D.; Price, Theodore J.; Campbell, Zachary T.Nociceptors rely on cap-dependent translation to rapidly induce protein synthesis in response to pro-inflammatory signals. Comparatively little is known regarding the role of the regulatory factors bound to the 3' end of mRNA in nociceptor sensitization. Poly(A)-binding protein (PABP) stimulates translation initiation by bridging the Poly(A) tail to the eukaryotic initiation factor 4F complex associated with the mRNA cap. Here, we use unbiased assessment of PABP binding specificity to generate a chemically modified RNA-based competitive inhibitor of PABP. The resulting RNA mimic, which we designated as the Poly(A) SPOT-ON, is more stable than unmodified RNA and binds PABP with high affinity and selectivity in vitro. We show that injection of the Poly(A) SPOT-ON at the site of an injury can attenuate behavioral response to pain. Collectively, these results suggest that PABP is integral for nociceptive plasticity. The general strategy described here provides a broad new source of mechanism-based inhibitors for RNA-binding proteins and is applicable for in vivo studies.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.