Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice
| Autor: | Rivat, Cyril, Sar, Chamroeun, Mechaly, Ilana, Leyris, Jean-Philippe, Diouloufet, Lucie, Sonrier, Corinne, Philipson, Yann, Lucas, Olivier, Mallié, Sylvie, Jouvenel, Antoine, Tassou, Adrien, Haton, Henri, Venteo, Stéphanie, Pin, Jean-Philippe, Trinquet, Eric, Charrier-Savournin, Fabienne, Mezghrani, Alexandre, Joly, Willy, Mion, Julie, Schmitt, Martine, Pattyn, Alexandre, Marmigère, Frédéric, Sokoloff, Pierre, Carroll, Patrick, Rognan, Didier, Valmier, Jean |
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| Přispěvatelé: | Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire d'Innovation Thérapeutique (LIT), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), ROGNAN, Didier |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Sensory Receptor Cells
Science [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology [SDV]Life Sciences [q-bio] Blotting Western Real-Time Polymerase Chain Reaction Article Mice fluids and secretions hemic and lymphatic diseases Ganglia Spinal Animals RNA Small Interfering lcsh:Science Cells Cultured In Situ Hybridization ComputingMilieux_MISCELLANEOUS [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology Peripheral Nervous System Diseases hemic and immune systems Immunohistochemistry Mice Inbred C57BL fms-Like Tyrosine Kinase 3 embryonic structures Neuralgia lcsh:Q |
| Zdroj: | Nature Communications Nature Communications, Nature Publishing Group, 2018, 9 (1), ⟨10.1038/s41467-018-03496-2⟩ Nature Communications, Nature Publishing Group, 2018, 9 (1), pp.1042. ⟨10.1038/s41467-018-03496-2⟩ Nature Communications, 2018, 9 (1), pp.1042. ⟨10.1038/s41467-018-03496-2⟩ Nature Communications, Vol 9, Iss 1, Pp 1-13 (2018) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-018-03496-2⟩ |
| Popis: | Peripheral neuropathic pain (PNP) is a debilitating and intractable chronic disease, for which sensitization of somatosensory neurons present in dorsal root ganglia that project to the dorsal spinal cord is a key physiopathological process. Here, we show that hematopoietic cells present at the nerve injury site express the cytokine FL, the ligand of fms-like tyrosine kinase 3 receptor (FLT3). FLT3 activation by intra-sciatic nerve injection of FL is sufficient to produce pain hypersensitivity, activate PNP-associated gene expression and generate short-term and long-term sensitization of sensory neurons. Nerve injury-induced PNP symptoms and associated-molecular changes were strongly altered in Flt3-deficient mice or reversed after neuronal FLT3 downregulation in wild-type mice. A first-in-class FLT3 negative allosteric modulator, discovered by structure-based in silico screening, strongly reduced nerve injury-induced sensory hypersensitivity, but had no effect on nociception in non-injured animals. Collectively, our data suggest a new and specific therapeutic approach for PNP. Sensitisation of dorsal root ganglia neurons contributes to neuropathic pain. Here the authors demonstrate the cytokine FL contributes to sensitisation of DRGs via its receptor FLT3 expressed on neurons, and identify a novel FLT3 inhibitor that attenuates neuropathic pain in mice. |
| Databáze: | OpenAIRE |
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