Format

Send to

Choose Destination
Nat Commun. 2018 Mar 12;9(1):1042. doi: 10.1038/s41467-018-03496-2.

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

Author information

1
Institute for Neurosciences of Montpellier, INSERM, Institut National de la Santé et de la Recherche Médicale, UMR1051, Hôpital Saint-Eloi, Montpellier, 34000, France.
2
Université de Montpellier, Montpellier, 34000, France.
3
Biodol Therapeutics, Cap Alpha, Clapiers, 34830, France.
4
Laboratoire d'Innovation Thérapeutique, UMR7200, CNRS-Université de Strasbourg, Illkirch, 67400, France.
5
Institut de Génomique Fonctionnelle, CNRS, INSERM, Univ. Montpellier, 34094, Montpellier, France.
6
Cisbio Bioassays, Parc Marcel Boiteux, BP84175, 30200, Codolet, France.
7
Laboratoire d'Innovation Thérapeutique, UMR7200, CNRS-Université de Strasbourg, Illkirch, 67400, France. rognan@unistra.fr.
8
Institute for Neurosciences of Montpellier, INSERM, Institut National de la Santé et de la Recherche Médicale, UMR1051, Hôpital Saint-Eloi, Montpellier, 34000, France. jean.valmier@umontpellier.fr.
9
Université de Montpellier, Montpellier, 34000, France. jean.valmier@umontpellier.fr.

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.

PMID:
29531216
PMCID:
PMC5847526
DOI:
10.1038/s41467-018-03496-2
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center