Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice

Abstract : 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.
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https://hal.umontpellier.fr/hal-02073206
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Soumis le : mardi 19 mars 2019 - 16:32:29
Dernière modification le : lundi 8 juillet 2019 - 13:22:08

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Cyril Rivat, Chamroeun Sar, Ilana Mechaly, Jean-Philippe Leyris, Lucie Diouloufet, et al.. Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice. Nature Communications, Nature Publishing Group, 2018, 9 (1), pp.1042. ⟨10.1038/s41467-018-03496-2⟩. ⟨hal-02073206⟩

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