RESUMEN
Lactate transport is an important means of communication between astrocytes and neurons and is implicated in a variety of neurobiological processes. However, the connection between astrocyte-neuron lactate transport and nociceptive modulation has not been well established. Here, we found that Complete Freund's adjuvant (CFA)-induced inflammation pain leads to a significant increase in extracellular lactate levels in the anterior cingulate cortex (ACC). Inhibition of glycogenolysis and lactate release in the ACC disrupted the persistent, but not acute, inflammation pain induced by CFA, and this effect was reversed by exogenous L-lactate administration. Knocking down the expression of lactate transporters (MCT1, MCT4, or MCT2) also disrupted the long lasting inflammation pain induced by CFA. Moreover, glycogenolysis in the ACC is critical for the induction of molecular changes related to neuronal plasticity, including the induction of phospho- (p-) ERK, p-CREB, and Fos. Taken together, our findings indicate that astrocyte-neuron lactate transport in the ACC is critical for the occurrence of persistent inflammation pain, suggesting a novel mechanism underlying chronic pain.
Asunto(s)
Arabinosa/farmacología , Comunicación Celular/inmunología , Dolor Crónico/inmunología , Giro del Cíngulo/patología , Iminofuranosas/farmacología , Ácido Láctico/metabolismo , Alcoholes del Azúcar/farmacología , Animales , Arabinosa/uso terapéutico , Astrocitos/metabolismo , Comunicación Celular/efectos de los fármacos , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/patología , Modelos Animales de Enfermedad , Adyuvante de Freund/administración & dosificación , Adyuvante de Freund/inmunología , Glucogenólisis/efectos de los fármacos , Glucogenólisis/inmunología , Giro del Cíngulo/citología , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/inmunología , Humanos , Iminofuranosas/uso terapéutico , Masculino , Ratones , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/inmunología , Neuronas/metabolismo , Alcoholes del Azúcar/uso terapéuticoRESUMEN
Beyond storing and supplying energy in the liver and muscles, glycogen also plays critical roles in cell differentiation, signaling, redox regulation, and stemness under various physiological and pathophysiological conditions. Such versatile functions have been revealed by various forms of glycogen storage diseases. Here, we outline the source of carbon flux in glycogen metabolism and discuss how glycogen metabolism guides CD8+ T-cell memory formation and maintenance. Likewise, we review how this affects macrophage polarization and inflammatory responses. Furthermore, we dissect how glycogen metabolism supports tumor development by promoting tumor-repopulating cell growth in hypoxic tumor microenvironments. This review highlights the essential role of the gluconeogenesis-glycogenesis-glycogenolysis-PPP metabolic chain in redox homeostasis, thus providing insights into potential therapeutic strategies against major chronic diseases including cancer.