Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice
Mar 12, 2018·
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Rivat, C.
Sar, C.
Mechaly, I.
Leyris, J.
Diouloufet, L.
Sonrier, C.
Philipson, Y.
Lucas, O.
Mallié, S.
Jouvenel, A.
Tassou, A.
Haton, H.
Venteo, S.
Pin, J.
Trinquet, E.
Charrier-Savournin, F.
Mezghrani, A.
Joly, W.
Mion, J.
Schmitt, M.
Pattyn, A.
Marmigère, F.
Sokoloff, P.
Carroll, P.
Rognan, D.
Valmier, J.
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.
Type
Publication
Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice, Nature Communications 2018 9 (1), 1042-