Tagne Alex Mabou, Fotio Yannick, Lee Hye-Lim, Jung Kwang-Mook, Katz Jean, Ahmed Faizy, Le Johnny, Bazinet Richard, Jang Cholsoon, Piomelli Daniele
Department of Anatomy and Neurobiology, University of California Irvine, Irvine, CA, USA.
Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.
bioRxiv. 2025 Feb 1:2025.01.30.635746. doi: 10.1101/2025.01.30.635746.
Acute injuries can progress into painful states that endure long after healing. The mechanism underlying this transition remains unclear, but metabolic adaptations to the bioenergy demands imposed by injury are plausible contributors. Here we show that peripheral injury activates AKT/mTORC1 in afferent segments of the mouse spinal cord, redirecting local core metabolism toward biomass production while simultaneously suppressing autophagy-mediated biomass reclamation. This metabolic shift supports neuroplasticity, but creates a resource bottleneck that depletes critical spinal cord nutrients. Preventing this depletion with a modified diet normalizes biomass generation and autophagy and halts the transition to chronic pain. This effect, observed across multiple pain models, requires activation of the nutrient sensors, sirtuin-1 and AMPK, as well as restoration of autophagy. The findings identify metabolic reprogramming as a key driver of the progression to pain chronicity and point to nutritional and pharmacological interventions that could prevent this progression after surgery or other physical traumas.
急性损伤可能会发展为在愈合后仍持续很长时间的疼痛状态。这种转变背后的机制尚不清楚，但对损伤所施加的生物能量需求的代谢适应可能是促成因素。在这里，我们表明外周损伤会激活小鼠脊髓传入节段中的AKT/mTORC1，将局部核心代谢导向生物量生成，同时抑制自噬介导的生物量回收。这种代谢转变支持神经可塑性，但会造成资源瓶颈，耗尽脊髓关键营养素。用改良饮食防止这种消耗可使生物量生成和自噬正常化，并阻止向慢性疼痛的转变。在多种疼痛模型中观察到的这种效应需要激活营养传感器、沉默调节蛋白-1和AMPK，以及恢复自噬。这些发现确定代谢重编程是疼痛慢性化进展的关键驱动因素，并指出了可在手术或其他身体创伤后预防这种进展的营养和药物干预措施。
