Neuron-astrocyte metabolic coupling facilitates spinal plasticity and maintenance of persistent pain

Long-lasting pain stimuli can trigger maladaptive changes in the spinal cord, reminiscent of plasticity associated with memory formation. Metabolic coupling between astrocytes and neurons has been implicated in neuronal plasticity and memory formation in the CNS, but neither its involvement in pathological pain nor in spinal plasticity has been tested. Here, we report a novel form of neuroglia signaling involving spinal astrocytic glycogen dynamics triggered by persistent noxious stimulation via upregulation of the metabolic signaling molecule PTG exclusively in spinal astrocytes. PTG drove glycogen build-up in astrocytes, and blunting glycogen accumulation and turnover by Ptg gene deletion reduced pain-related behaviors and promoted faster recovery by shortening pain maintenance. Furthermore, mechanistic analyses revealed that glycogen dynamics is a critically required process for maintenance of pain by facilitating neuronal plasticity in spinal lamina 1 neurons. Finally, metabolic analysis indicated that glycolysis and lactate transfer between astrocytes and neurons fuels spinal neuron hyperexcitability. Spinal glycogen-metabolic cascades therefore hold therapeutic potential to alleviate pathological pain.