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Metabolic Competition Between Microglia and Neurons as Driver of Chronic Pain
Enso O Torres Alegre1, Diana E Mora Jiménez2
1Pontifical Catholic University of Chile, Santiago, Chile. onill@uc.cl.
Abstract:
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.
Insights
Microglia metabolic reprogramming, not just inflammation, may drive chronic pain. Competition for energy resources like glucose and NAD+ between microglia and neurons could sustain pain signaling, offering new therapeutic targets.
Area of Science:
- Neuroscience
- Immunology
- Metabolic Biology
Background:
- Chronic pain is linked to neuroinflammation and synaptic changes.
- Microglial activation involves significant metabolic shifts, including altered glucose metabolism and mitochondrial function.
- The role of microglial metabolic reprogramming in pain neurobiology is understudied.
Purpose of the Study:
- To propose metabolic competition between activated microglia and neurons as a novel mechanism in chronic pain.
- To explore how shifts in local energy metabolites (glucose, lactate, NAD+) influence neuronal excitability and central sensitization.
- To integrate immunometabolism and metabolic neurobiology for new therapeutic strategies in pain management.
Main Methods:
- Review and integration of advances in immunometabolism.
- Application of emerging single-cell and spatial metabolomics techniques.
- Utilization of in vivo biosensor imaging for metabolic analysis.
Main Results:
- Activated microglia undergo metabolic reprogramming, shifting towards glycolysis.
- Competition for metabolites like glucose and NAD+ between microglia and neurons may sustain pain.
- Metabolic alterations can modulate neuronal excitability and central sensitization independently of classical inflammatory signals.
Conclusions:
- Cellular metabolism represents an underexplored therapeutic target for chronic pain.
- Metabolic competition offers a new framework for understanding persistent pain states.
- Targeting microglial metabolism could provide novel avenues for chronic pain management.
