RESUMEN
Painful peripheral neuropathy is a severe side effect in oxaliplatin therapy that compromises cancer patients' quality of life. However, its underlying pathogenic mechanisms remain largely unknown. Here, we found that intraperitoneal consecutive administration of oxaliplatin significantly increased excitability of small diameter dorsal root ganglion neurons and induced thermal hyperalgesia in rats. Furthermore, the CX3CL1 expression was significantly increased after oxaliplatin treatment, and intrathecal injection of a neutralizing antibody against CX3CL1 markedly attenuated the enhanced excitability of dorsal root ganglion neurons and thermal hyperalgesia. Importantly, the upregulated CX3CL1 is mediated by the NF-κB signaling pathway, as inhibition of NF-κB p65 activation with pyrrolidine dithiocarbamate or p65 siRNA inhibited the upregulation of CX3CL1, the enhanced excitability of dorsal root ganglion neurons, and thermal hyperalgesia induced by oxaliplatin. Further studies with chromatin immunoprecipitation found that oxaliplatin treatment increased the recruitment of NF-κB p65 to the CX3Cl1 promoter region. Our results suggest that upregulation of CX3CL1 in dorsal root ganglion mediated by NF-κB activation contributes to the peripheral sensitization and chronic pain induced by oxaliplatin administration.
Asunto(s)
Quimiocina CX3CL1/genética , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/genética , Ganglios Espinales/metabolismo , FN-kappa B/metabolismo , Compuestos Organoplatinos/uso terapéutico , Regulación hacia Arriba , Animales , Quimiocina CX3CL1/metabolismo , Ganglios Espinales/efectos de los fármacos , Hiperalgesia , Masculino , Neuronas/metabolismo , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/farmacología , Oxaliplatino , Fosforilación/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Ratas Sprague-Dawley , Factor de Transcripción ReIA/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The important Ca(2+)-sensing protein, calmodulin (CaM), plays its role in regulating cellular responses by activating specific CaM-binding proteins (CaMBPs), and therefore the study of the latter is an important way to know the mechanism of CaM and elucidate the Ca(2+)-CaM signal transduction pathway. More than fifty kinds of CaMBPs have been identified in plant kingdom. CaMBPs are distributed in all plant species and all kinds of tissues; they are involved in many biological responses during the processes of growth and development, metabolism regulation and cell division, such as responses to phytohormones, to stress, and to pathogen, and transcription activation. This review summarizes the recent progress on the interaction of CaMBPs with CaM, their distribution, their subcellular localization, and involvement in biological functions.