Translatome analysis reveals altered spinal astrocyte metabolism in acute and chronic pain

Chronic pain affects an estimated 20% of people globally, but the mechanisms that differentiate acute pain from chronic pain are not well understood. Astrocytes regulate neuronal signaling in physiological conditions and can drive neuroinflammation in pain states, likely contributing to pain progression. It is therefore important to determine how astrocyte cellular and molecular pathways change in response to pain-inducing peripheral injury, and to identify critical timepoints of astrocyte involvement in pain progression. Here, we utilize translating ribosome affinity purification technology in a mouse model of complex regional pain syndrome to uncover the molecular signature of spinal astrocytes in early (acute) and late (chronic) post-injury phases. We find that astrocytes exhibit a temporally distinct translatomic signature, with the most significant gene expression changes occurring early after injury. We further identify astrocyte lipid metabolism and oxidative phosphorylation as key dysregulated pathways after injury, and discover that orlistat, a clinically approved weight loss drug that reduces systemic lipid load, prevents the development of chronic pain in CRPS mice. Overall, this work highlights the importance of astrocyte lipid metabolism in pain pathophysiology and suggests that targeting this pathway may have therapeutic potential.