Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore, Maryland 21201.
Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore, Maryland 21201
J Neurosci. 2024 Nov 20;44(47):e1442242024. doi: 10.1523/JNEUROSCI.1442-24.2024.
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. 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.
慢性疼痛仍然是一个严重的健康挑战，目前的治疗方法效果有限。本研究旨在探讨疼痛进展和缓解的代谢变化，揭示感觉神经元中一种新的代偿机制。我们使用雄性小鼠的痛觉过敏引发模型，证明神经生长因子（NGF）最初破坏了线粒体丙酮酸氧化，导致急性痛觉过敏。令人惊讶的是，即使在痛觉过敏明显缓解后，这种代谢紊乱仍然持续存在。我们发现，在缓解阶段，感觉神经元在背根神经节中表现出谷氨酰胺氧化增加和主要谷氨酰胺转运体 ASCT2 的上调。这种代偿反应在疼痛缓解中起着至关重要的作用，这可以通过我们的实验来证明。ASCT2 的敲低阻止了 NGF 诱导的痛觉过敏的缓解，并促使其向慢性状态转变。此外，我们表明，谷氨酰胺分解产物α-酮戊二酸可减轻痛觉过敏引发模型的急性和慢性阶段的糖酵解通量和痛觉过敏。ASCT2 在转化模型中的重要性也得到了进一步证实，其中其敲低阻止了足底切口后痛觉过敏的缓解。这些发现强调了代谢变化在疼痛缓解中的关键作用，并确定了 ASCT2 介导的谷氨酰胺代谢作为慢性疼痛的潜在治疗靶点。了解这些促进疼痛缓解的内源性机制可以指导开发新的干预措施，以防止疼痛从急性向慢性转变。
