Astrocytic glycogenolysis gates Warburg-like metabolic reprogramming that promotes neuropathic pain chronification
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Chronic pain remains a major unmet medical challenge, yet the metabolic checkpoints that govern its persistence are poorly defined. Astrocytes are increasingly recognized as chemically programmable hubs that tune neuronal excitability through metabolic circuits. Building on reports that astrocyte–neuron lactate shuttling (ANLS) in the anterior cingulate cortex (ACC) supports chronic pain, we asked how astrocytic metabolic states evolve over the course of pain chronification. Using untargeted metabolomics of the ACC combined with GFAP-RiboTag–based astrocyte-specific transcriptomics, we provide a time-resolved map of astrocytic metabolism across the transition from acute nociception to chronic neuropathic pain. This analysis reveals a biphasic glycogen program—an acute glycogenolysis-triggered glycogen supercompensation—that culminates in the emergence of a Warburg-like metabolic signature with tissue acidification associated with sustained lactate shuttling and persistent circuit activation. Using glycogen phosphorylase inhibitors (GPI-1, GPI-2) as pharmacological probes, we show that early glycogenolysis blockade attenuates this Warburg-like shift, partially normalizes ACC metabolic signatures, and reduces long-lasting mechanical hypersensitivity, without impairing acute nociceptive sensitization. These findings identify astrocytic metabolic reprogramming as a pharmacologically tractable circuit-level process and nominate glycogenolysis as an upstream biochemical gate and potential therapeutic control point in neuropathic pain.
HIGHLIGHTS
Most experimental models of chronic pain emphasize progressive sensitization, yet few have identified a chemically tractable switch that converts transient nociception into a persistent cortical state. Here, we propose astrocytic glycogenolysis as such a switch—a gatekeeper process whose brief engagement can reconfigure neuroglial metabolism toward a Warburg-like signature that stabilizes hyperexcitable circuit dynamics. By leveraging small-molecule glycogen phosphorylase inhibitors as mechanistic precision probes, we move beyond correlation to delineate a pathway-level control architecture that can be transiently perturbed to dissociate acute nociceptive processing from pain chronification. This framework reframes astrocytes from metabolic support cells to state-setting regulators of cortical excitability and positions glycogenolysis as a therapeutically actionable leverage point. More broadly, our findings underscore a methodological opportunity: applying chemical biology to neuroglial metabolism can expose governing checkpoints that are often obscured by descriptive physiology, enabling mechanism-first, pathway-directed intervention strategies across neurological disease contexts.
