Glutamine Oxidation in Mouse Dorsal Root Ganglia Regulates Pain Resolution and Chronification.

Chronic pain remains a significant health challenge with limited effective treatments. This study investigates the metabolic changes underlying pain progression and resolution, uncovering a novel compensatory mechanism in sensory neurons. Using the hyperalgesic priming model in male mice, we demonstrate that nerve growth factor (NGF) initially disrupted mitochondrial pyruvate oxidation, leading to acute allodynia. Surprisingly, this metabolic disruption persisted even after the apparent resolution of allodynia. We discovered that during the resolution phase, sensory neurons exhibit increased glutamine oxidation and upregulation of the major glutamine transporter ASCT2 in dorsal root ganglia (DRGs). This compensatory response plays a crucial role in pain resolution, as demonstrated by our experiments. Knockdown of ASCT2 prevents the resolution of NGF-induced allodynia and precipitates the transition to a chronic state. Furthermore, we show that the glutamine catabolite α-ketoglutarate attenuated glycolytic flux and alleviated allodynia in both acute and chronic phases of the hyperalgesic priming model. The importance of ASCT2 is further confirmed in a translational model, where its knockdown prevented the resolution of allodynia following plantar incision. These findings highlight the pivotal role of metabolic changes in pain resolution and identify ASCT2-mediated glutamine metabolism as a potential therapeutic target for chronic pain. Understanding these endogenous mechanisms that promote pain resolution can guide the development of novel interventions to prevent the transition pain from acute to chronic.Significance Statement Chronic pain is a widespread health issue with limited effective treatments. This study unveils a critical metabolic mechanism in sensory neurons that determines whether acute pain resolves or becomes chronic. We discovered that pain resolution depends on a compensatory increase in glutamine metabolism, mediated by the transporter ASCT2, rather than normalization of initial metabolic disruptions. This finding significantly advances our understanding of pain chronification and identifies a novel therapeutic target. By elucidating how the body naturally resolves pain, we open new avenues for developing treatments that could prevent acute pain from transitioning to chronic pain or treat existing chronic pain. This research has the potential to transform pain management strategies and improve quality of life for millions of pain sufferers.