Metabolic Competition Between Microglia and Neurons as Driver of Chronic Pain

Chronic pain is traditionally framed as a consequence of neuroinflammation and maladaptivesynaptic plasticity, with activated microglia releasing cytokines, chemokines, and growth factorsthat sensitize nociceptive circuits in the spinal dorsal horn. However, microglial activation isalso accompanied by profound metabolic reprogramming—including a glycolytic shift, alteredmitochondrial dynamics, and increased demand for biosynthetic intermediates—that has receivedcomparatively little attention in pain neurobiology. Here we propose that metabolic competitionbetween activated microglia and neighboring neurons may constitute an underexplored mechanismcontributing to persistent pain states. We argue that shifts in local energy allocation—particularlyglucose, lactate, and NAD+ availability—could modulate neuronal excitability and sustain centralsensitization even when classical inflammatory signaling is no longer dominant. Drawing onadvances in immunometabolism, emerging single-cell/spatial metabolomics, and in vivo biosensorimaging, we integrate neuroimmunology with metabolic neurobiology to generate experimentallytestable predictions. If validated, this framework could reposition cellular metabolism as atractable therapeutic dimension for chronic pain management.