A metabolic switch in astrocytes converts nociceptive injury into persistent pain

Chronic pain is not simply the prolonged presence of acute pain. It is a pathological transition in which transient nociceptive input becomes stabilized within central circuits. Yet much of the field has examined chronic pain as an established endpoint. What has remained largely invisible is the process of chronification itself: how the brain moves from an acute pain state to a persistent pathological state.

This gap is particularly important in the anterior cingulate cortex (ACC), a key cortical hub for pain persistence. Previous studies have implicated astrocyte-derived lactate and astrocyte–neuron metabolic coupling in chronic pain. However, lactate has often been interpreted mainly as an increased energetic substrate supplied to overactive neurons. This view does not explain when the lactate-associated state emerges, whether it develops linearly, or what upstream event commits astrocytes to a chronic pain-supporting metabolic phenotype.

Our study addresses this problem by introducing time as a central dimension. Using time-resolved untargeted metabolomics of the ACC together with astrocyte-specific transcriptomic profiling, we followed the metabolic trajectory from acute nociception to chronic neuropathic pain. This approach revealed that pain chronification is not accompanied by a simple, linear increase in metabolic activity. Instead, ACC astrocytes undergo a distinctly biphasic metabolic program: early glycogenolysis, subsequent glycogen supercompensation, and delayed glycolytic/lactate-associated reprogramming as pain becomes chronic.

A major conceptual advance of this work is the application of untargeted GC-MS metabolomics to map the temporal evolution of ACC metabolism during neuropathic pain progression. Rather than measuring selected metabolites at a single chronic time point, we captured the dynamic metabolic landscape across the transition itself. This analysis revealed that the chronic phase is marked by a Warburg-like signature, a metabolic concept classically discussed in cancer biology and immune activation, but not previously framed as a time-dependent astrocytic program in the ACC pain circuit.

This finding changes how lactate metabolism in chronic pain should be understood. The relevant phenotype is not merely increased energy production for neurons. Rather, astrocytes acquire a glycolytic bias, resembling a Warburg-like state, in which lactate-associated metabolism becomes part of a broader and stabilized pathological program. In this framework, lactate is not just fuel; it is a readout and mediator of a disease-associated metabolic state that helps sustain persistent circuit activation.

The key upstream node in this process is glycogenolysis. Brain glycogen is highly enriched in astrocytes, but its temporal role in pain chronification had not been defined. We found that astrocytic glycogen metabolism follows a nonlinear sequence rather than a steady increase or decrease. Early glycogen breakdown appears to trigger a supercompensation-like glycogen response, which then permits the later emergence of the Warburg-like chronic state. Thus, glycogenolysis acts as a metabolic gate that opens the path from transient injury to persistent pain-associated reprogramming.

This was not only a correlative observation. By pharmacologically inhibiting glycogen phosphorylase in the ACC immediately after nerve injury, we interrupted the cascade at its upstream point. This prevented the full development of glycogen supercompensation, suppressed the later Warburg-like metabolic signature, reduced lactate-associated metabolic remodeling, and shifted the ACC away from the chronic pain metabolic state. These results identify glycogenolysis as a chemically tractable gatekeeper of pain chronification.

The behavioral result is particularly important. Blocking this metabolic gate did not simply suppress pain in a nonspecific manner. Acute nociceptive sensitization was largely preserved, whereas persistent mechanical hypersensitivity was selectively attenuated. This distinction indicates that astrocytic glycogenolysis is not required for the initial detection of injury-induced pain, but is critical for the conversion of acute pain into chronic pain. In other words, this study identifies a node that selectively controls pain persistence rather than acute protective nociception.

The same intervention also reached beyond metabolism. Inhibiting glycogenolysis reduced pathological neuronal activation in the ACC and modulated multiple activity-related markers and downstream pain-associated circuits. This places astrocytic glycogenolysis at an important intersection between metabolic state, neuronal activation, and circuit-level persistence. The pathway is therefore not merely a biochemical curiosity; it is a control point capable of influencing the cellular and circuit mechanisms that maintain chronic pain.

Together, our findings support a revised model of pain chronification. Peripheral nerve injury first engages astrocytic glycogenolysis in the ACC. This early event drives a biphasic glycogen response and enables a delayed Warburg-like glycolytic bias. Once established, this astrocytic metabolic phenotype supports persistent neuronal hyperactivity and chronic pain behavior. Blocking the gate prevents the chronic state from forming while sparing the acute pain response.

The broader implication is that chronic pain should be viewed not only as a disorder of neuronal excitability or inflammation, but also as a disorder of astrocytic metabolic state fixation. The transition to chronic pain depends on a temporally organized, nonlinear metabolic program. By revealing this program and identifying glycogenolysis as its chemical gatekeeper, this study provides a mechanistic entry point for selectively targeting pain chronification.

Reference

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