新陈代谢与细胞功能的各个方面有着千丝万缕的联系。除了能量产生和生物合成之外，新陈代谢在调节信号转导和基因表达方面也起着至关重要的作用。代谢状态的改变已被证明会维持异常的信号传导和转录，从而导致癌症、心血管疾病和神经退行性疾病等疾病。代谢基因多态性和缺陷也与慢性疼痛相关，神经生长因子 (NGF) 水平升高也是如此。然而，NGF 调节感觉神经元代谢的机制仍不清楚。这项研究表明足底内 NGF 注射可重新编程感觉神经元代谢。神经生长因子抑制线粒体丙酮酸氧化并增强乳酸排出，需要 24 小时才能增加乳酸脱氢酶 A 和丙酮酸脱氢酶激酶 1 (PDHK1) 的表达。抑制这些代谢酶可以逆转 NGF 介导的作用。值得注意的是，直接破坏线粒体丙酮酸氧化会引起严重、持续的异常性疼痛，表明这种代谢功能障碍与慢性疼痛有关。 Poly(A) mRNA 的纳米孔长读长测序揭示了代谢破坏时的广泛转录组变化，包括基因表达、剪接和 Poly(A) 尾长度的改变。通过将背根神经节的代谢紊乱与转录组重编程联系起来，这项研究增强了我们对持续伤害性敏化背后机制的理解。这些发现表明，线粒体丙酮酸氧化受损可能会导致慢性疼痛，可能是通过影响转录组调节来实现的。进一步探索这些代谢物驱动的机制可能会揭示顽固性疼痛的新治疗靶点。版权所有 © 2024 作者。由 Wolters Kluwer Health, Inc. 代表国际疼痛研究协会出版。

Metabolism is inextricably linked to every aspect of cellular function. In addition to energy production and biosynthesis, metabolism plays a crucial role in regulating signal transduction and gene expression. Altered metabolic states have been shown to maintain aberrant signaling and transcription, contributing to diseases like cancer, cardiovascular disease, and neurodegeneration. Metabolic gene polymorphisms and defects are also associated with chronic pain conditions, as are increased levels of nerve growth factor (NGF). However, the mechanisms by which NGF may modulate sensory neuron metabolism remain unclear. This study demonstrated that intraplantar NGF injection reprograms sensory neuron metabolism. Nerve growth factor suppressed mitochondrial pyruvate oxidation and enhanced lactate extrusion, requiring 24 hours to increase lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 (PDHK1) expression. Inhibiting these metabolic enzymes reversed NGF-mediated effects. Remarkably, directly disrupting mitochondrial pyruvate oxidation induced severe, persistent allodynia, implicating this metabolic dysfunction in chronic pain. Nanopore long-read sequencing of poly(A) mRNA uncovered extensive transcriptomic changes upon metabolic disruption, including altered gene expression, splicing, and poly(A) tail lengths. By linking metabolic disturbance of dorsal root ganglia to transcriptome reprogramming, this study enhances our understanding of the mechanisms underlying persistent nociceptive sensitization. These findings imply that impaired mitochondrial pyruvate oxidation may drive chronic pain, possibly by impacting transcriptomic regulation. Exploring these metabolite-driven mechanisms further might reveal novel therapeutic targets for intractable pain.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.