Glycometabolism Reprogramming of Glial Cells in Central Nervous System: Novel Target for Neuropathic Pain

Abstract

Neuropathic pain is characterized by hyperalgesia and allodynia. Inflammatory response is conducive to tissue recovery upon nerve injury, but persistent and exaggerated inflammation is detrimental and participates in neuropathic pain. Synaptic transmission in the nociceptive pathway, and particularly the balance between facilitation and inhibition, could be affected by inflammation, which in turn is regulated by glial cells. Importantly, glycometabolism exerts a vital role in the inflammatory process. Glycometabolism reprogramming of inflammatory cells in neuropathic pain is characterized by impaired oxidative phosphorylation in mitochondria and enhanced glycolysis. These changes induce phenotypic transition of inflammatory cells to promote neural inflammation and oxidative stress in peripheral and central nervous system. Accumulation of lactate in synaptic microenvironment also contributes to synaptic remodeling and central sensitization. Previous studies mainly focused on the glycometabolism reprogramming in peripheral inflammatory cells such as macrophage or lymphocyte, little attention was paid to the regulation effects of glycometabolism reprogramming on the inflammatory responses in glial cells. This review summarizes the evidences for glycometabolism reprogramming in peripheral inflammatory cells, and presents a small quantity of present studies on glycometabolism in glial cells, expecting to promote the exploration in glycometabolism in glial cells of neuropathic pain.

The potential role of T-cell metabolism-related molecules in chronic neuropathic pain after nerve injury: a narrative review

“…These alterations induced a diverse range of effects on the cells in that environment, such as facilitating the conversion of inflammatory phenotypes ( 38 ) and triggering oxidative stress ( 39 ). Recent studies showed that metabolic abnormalities could occur in this microenvironment ( 40 ), which theoretically could modify neuropathic pain if rectified ( 41 ). Interestingly, metabolic abnormalities could also exist in T cells.…”

“…The enhancement of glucose metabolism implies that there might be a temporary decrease in glucose within the microenvironment. These metabolic alterations result in the accumulation of various intermediates, including phosphoenolpyruvate (PEP) ( 41 , 49 ) and lactate ( 41 , 49 , 50 ), which subsequently disturb the acid-base equilibrium in the microenvironment, driving a cascade of pathophysiological processes ( 41 ). Of note, astrocytes can produce L-lactate through the astrocyte-neuron lactate shuttle (ANLS), playing a crucial role in maintaining synaptic transmission ( 51 , 52 ).…”

“…Lactate can shuttle between glial cells and neurons, acting as one of the essential energy sources for neurons in the context of nerve injury, in order to maintain and promote pain transmission ( 51 ). Furthermore, Glutamate can be taken up by various cells and increase the metabolism of glutamine ( 41 , 61 , 62 ). It is noteworthy that, besides enhancing the metabolism of glutamate, glutamine also facilitates anaerobic glycolysis.…”

“…It is noteworthy that, besides enhancing the metabolism of glutamate, glutamine also facilitates anaerobic glycolysis. Glutamate can be taken up by astrocytes via a sodium-dependent mechanism, which increases the intracellular sodium concentration, activates the sodium-potassium-ATPase on the cell membrane, promotes glucose uptake, and thus promotes anaerobic glycolysis ( 41 ). Furthermore, the presence of IFN-γ within the microenvironment has been implicated in potential modulatory effects on microglial cells ( 63 ).…”

Lyn‐mediated glycolysis enhancement of microglia contributes to neuropathic pain through facilitating IRF5 nuclear translocation in spinal dorsal horn

“…Recent studies focused on the key influences of abnormal glycometabolism in neurons and supporting cells induced by chronic nerve injury. As is generally understood, energy metabolism is the core process in providing energy and substrates for signal transmission and cell responses, and glycolysis is the basis activity of cell energy metabolism 5 . Microglia are widely present in central nervous system and involved in various neurophysiological processes including neuronal development, synaptic remodelling and immune response.…”