RESUMEN
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.
Asunto(s)
Enfermedades del Sistema Nervioso Periférico/metabolismo , Tirosina Quinasa 3 Similar a fms/metabolismo , Animales , Western Blotting , Células Cultivadas , Ganglios Espinales/metabolismo , Inmunohistoquímica , Hibridación in Situ , Ratones , Ratones Endogámicos C57BL , Neuralgia/genética , Neuralgia/metabolismo , Enfermedades del Sistema Nervioso Periférico/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Células Receptoras Sensoriales/metabolismo , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
The palladium-catalyzed alkoxycarbonylation of an α-chloro ketone can be efficiently combined to a Michael addition reaction in a new two-step domino reaction, allowing the synthesis of original highly functionalized α-alkylated ß-ketoesters. The scope of the reaction was extended to several α-chloro ketones and Michael acceptors with moderate to very good yields.