Temporal astrocytic metabolic reprogramming gates pain chronification.

Most experimental models of chronic pain emphasize the gradual emergence of sensory hypersensitivity, yet pain chronification can also be conceptualized as a metabolically regulated state transition. In this review, we synthesize evidence mainly from mouse and rat spinal cord and anterior cingulate cortex studies indicating that astrocytes temporally coordinate neuronal excitability, inflammatory signaling, and metabolic coupling. We propose that chronification proceeds through temporally organized astrocytic metabolic remodeling: GPCR-linked lactate-coupled signaling during acute induction, sustained glycolytic gene expression and glycogen remodeling during consolidation, and stabilization of pain-permissive astrocyte states through lactylation-linked inflammatory and chromatin regulation. By integrating these mechanisms along a temporal axis, this framework distinguishes processes that initiate chronicity from those that maintain established pain and suggests stage-specific logic for future interventions.