Metabolic Competition Between Microglia and Neurons as Driver of Chronic Pain

Chronic pain is traditionally framed as a consequence of neuroinflammation and maladaptive synaptic plasticity, with activated microglia releasing cytokines, chemokines, and growth factors that sensitize nociceptive circuits in the spinal dorsal horn. However, microglial activation is also accompanied by profound metabolic reprogramming-including a glycolytic shift, altered mitochondrial dynamics, and increased demand for biosynthetic intermediates-that has received comparatively little attention in pain neurobiology. Here, we propose that metabolic competition between activated microglia and neighboring neurons may constitute an underexplored mechanism contributing to persistent pain states. We argue that shifts in local energy allocation-particularly glucose, lactate, and nicotinamide adenine dinucleotide (NAD⁺) availability-could modulate neuronal excitability and sustain central sensitization even when classical inflammatory signaling is no longer dominant. Drawing on advances in immunometabolism, emerging single-cell/spatial metabolomics, and in vivo biosensor imaging, we integrate neuroimmunology with metabolic neurobiology to generate experimentally testable predictions. If validated, this framework could reposition cellular metabolism as a tractable therapeutic dimension for chronic pain management.