Browsing by Author "Barragán-Iglesias, Paulino"
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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 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 Some Prospective Alternatives for Treating Pain: The Endocannabinoid System and its Putative Receptors GPR18 and GPR55(Frontiers Media SA, 2019-01-08) Guerrero-Alba, Raquel; Barragán-Iglesias, Paulino; Gonzalez-Hernandez, Abimael; Valdez-Morales, Eduardo E.; Granados-Soto, Vinicio; Condes-Lara, Miguel; Rodriguez, Martin G.; Marichal-Cancino, Bruno A.; Barragán-Iglesias, PaulinoBackground: Marijuana extracts (cannabinoids) have been used for several millennia for pain treatment. Regarding the site of action, cannabinoids are highly promiscuous molecules, but only two cannabinoid receptors (CB₁ and CB₂) have been deeply studied and classified. Thus, therapeutic actions, side effects and pharmacological targets for cannabinoids have been explained based on the pharmacology of cannabinoid CB₁/CB₂ receptors. However, the accumulation of confusing and sometimes contradictory results suggests the existence of other cannabinoid receptors. Different orphan proteins (e.g., GPR18, GPR55, GPR119, etc.) have been proposed as putative cannabinoid receptors. According to their expression, GPR18 and GPR55 could be involved in sensory transmission and pain integration. Methods: This article reviews select relevant information about the potential role of GPR18 and GPR55 in the pathophysiology of pain. Results: This work summarized novel data supporting that, besides cannabinoid CB₁ and CB₂ receptors, GPR18 and GPR55 may be useful for pain treatment. Conclusion: There is evidence to support an antinociceptive role for GPR18 and GPR55.