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.
Highlights
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
Disruption of the blood–nerve barrier produced by nerve injury seems to be responsible for the presence of CD45 positive features of the ligand (FL)-expressing hematopoietic cells at the site of nerve lesion
We demonstrate that sensory neuron fms-like tyrosine kinase 3 receptor (FLT3) is necessary and sufficient for the development and maintenance of the PNP state
Summary
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. After nerve damage, TRPV1, a member of the TRP transducer family[9], with a well-established role in inflammatory pain, is upregulated in different models of PNP both at DRG peripheral and central synapses This upregulation is correlated with the development and the maintenance of thermal hypersensitivity[10]. Neuro-immune interactions are key regulators of local peripheral sensitization[13,14] They are mediated by immune cells, which invade the lesion site after nerve blood barrier permeabilization, secrete sensitizers (cytokines, chemokines, growth factors) that contribute to the development of the nerve injuryinduced hypersensitivity and the maintenance of PNP13,14. Flt3KO mice have a normal number of mature hematopoietic cells in all hematopoietic organs, even though some discrete populations of cell progenitors, but not more mature cells, are reduced[24]
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