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

Cyril Rivat, Chamroeun Sar, Ilana Mechaly, Jean-Philippe Leyris, Lucie Diouloufet, Corinne Sonrier, Yann Philipson, Olivier Lucas, Sylvie Mallié, Antoine Jouvenel, Adrien Tassou, Henri Haton, Stéphanie Venteo, Jean-Philippe Pin, Eric Trinquet, Fabienne Charrier-Savournin, Alexandre Mezghrani, Willy Joly, Julie Mion, Martine Schmitt, Alexandre Pattyn, Frédéric Marmigère, Pierre Sokoloff, Patrick Carroll, Didier Rognan () and Jean Valmier ()
Additional contact information
Cyril Rivat: Hôpital Saint-Eloi
Chamroeun Sar: Hôpital Saint-Eloi
Ilana Mechaly: Hôpital Saint-Eloi
Jean-Philippe Leyris: Hôpital Saint-Eloi
Lucie Diouloufet: Hôpital Saint-Eloi
Corinne Sonrier: Hôpital Saint-Eloi
Yann Philipson: CNRS-Université de Strasbourg
Olivier Lucas: Hôpital Saint-Eloi
Sylvie Mallié: Hôpital Saint-Eloi
Antoine Jouvenel: Hôpital Saint-Eloi
Adrien Tassou: Hôpital Saint-Eloi
Henri Haton: Hôpital Saint-Eloi
Stéphanie Venteo: Hôpital Saint-Eloi
Jean-Philippe Pin: Univ. Montpellier
Eric Trinquet: Parc Marcel Boiteux
Fabienne Charrier-Savournin: Parc Marcel Boiteux
Alexandre Mezghrani: Hôpital Saint-Eloi
Willy Joly: Hôpital Saint-Eloi
Julie Mion: Hôpital Saint-Eloi
Martine Schmitt: CNRS-Université de Strasbourg
Alexandre Pattyn: Hôpital Saint-Eloi
Frédéric Marmigère: Hôpital Saint-Eloi
Pierre Sokoloff: Cap Alpha
Patrick Carroll: Hôpital Saint-Eloi
Didier Rognan: CNRS-Université de Strasbourg
Jean Valmier: Hôpital Saint-Eloi

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03496-2

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DOI: 10.1038/s41467-018-03496-2

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