Short-lived, acute pain is a normal response to an injury and will steadily diminish as inflammation subsides. For some, however, this kind of pain develops into a chronic condition that persists for more than six months. Scientists have had little understanding of the underlying mechanisms that enable this progression.Now, researchers from the Center for Translational Immunology at the University Medical Center (UMC) Utrecht have identified the process that underpins this transition from acute to persistent inflammation, and found that boosting a type of vitamin B3 in cells – nicotinamide riboside – could mitigate this progression to chronic pain purgatory.Shining the spotlight on the mitochondria, which has previously been linked to chronic pain, the team looked at how inflammation impacted these cellular powerhouses.

短暂的急性疼痛是对损伤的正常反应，并且随着炎症消退将稳步减少。然而，对于一些人来说，这种疼痛发展成持续超过六个月的慢性病。科学家们对实现这一进展的潜在机制知之甚少。现在，乌得勒支大学医学中心（UMC）转化免疫学中心的研究人员已经确定了支持从急性炎症向持续性炎症转变的过程，并发现在细胞中增加一种维生素B3（烟酰胺核苷）可以减轻这种进展为慢性疼痛炼狱。将聚光灯照射在先前与慢性疼痛有关的线粒体上，研究小组研究了炎症如何影响这些细胞发电站。

What they found was that a change in mitochondrial and metabolic function in sensory neurons – the Dorsal root ganglion neurons (DRGs) – disrupts the inflammation pathway through which pain gets resolved over time.“Metabolic changes in sensory neurons result in failure of endogenous pain resolution pathways and drive the transition to chronic pain,” said Hanneke Willemen, a chronic pain researcher at UMC Utrecht.This kind of neuronal plasticity, called hyperalgesic priming, sees pain remain after the initial inflammatory trigger has dissipated.

他们发现感觉神经元（背根神经节神经元（DRGs））中线粒体和代谢功能的改变破坏了疼痛随时间消退的炎症途径。UMC乌得勒支的慢性疼痛研究人员Hanneke Willemen说：“感觉神经元的代谢变化导致内源性疼痛消退途径失败，并推动向慢性疼痛的转变。这种称为痛觉过敏引发的神经元可塑性看到疼痛依然存在在最初的炎症触发消散之后。

It’s particularly prevalent in people with inflammatory and mitochondrial diseases..

它在炎症和线粒体疾病患者中特别普遍。。

This graphic shows how in the mice study, animals boosted with nicotinamide riboside had their chronic pain pathway disruptedWillemen, H et al/Cell Reports Medicine/(CC By 4.0)

该图显示了在小鼠研究中，用烟酰胺核苷加强的动物如何破坏其慢性疼痛途径Willemen，H et al/Cell Reports Medicine/（CC By 4.0）

In a mice model, the researchers identified this process, seeing how hyperalgesic priming caused overactivity of the mitochondrial protein ATPSc-KMT, causing the changes in the sensory neurons. A previous study has also linked the increased expression of ATPSc-KMT to chronic pain.Here, researchers discovered that mice primed for this mitochondrial disturbance had low levels of nicotinamide riboside once the initial pain inflammatory response resolved.

在小鼠模型中，研究人员确定了这一过程，观察痛觉过敏引发如何引起线粒体蛋白ATPSc KMT的过度活跃，从而引起感觉神经元的变化。先前的研究还将ATPSc KMT的表达增加与慢性疼痛联系起来。在这里，研究人员发现，一旦最初的疼痛炎症反应消退，为这种线粒体紊乱引发的小鼠的烟酰胺核苷水平就会降低。

Nicotinamide riboside, which is changed in the body to a chemical called NAD+, is critical for maintaining proper mitochondrial function.The researchers found that by inhibiting mitochondrial respiration, reducing expression of the ATPSCKMT gene, or supplementing NAD+ metabolites through ramped-up nicotinamide riboside, chronic pain could be bypassed.In another group of mice that had experienced induced inflammation, a cohort that received nicotinamide riboside injections showed a slower response to pain stimuli, suggesting their hypersensitivity – a hallmark of chronic pain – had been regulated.The researchers believe further studies could lead to potential treatments that block chronic pain from developing, or reverse it when it does.“In our study we provide evidence that a peripheral inflammation induces persistent mitochondrial and metabolic changes in sensory neurons, which affects the ability of neurons to resolve from hyperalgesia induced by a subsequent inflammatory trigger,” the researchers noted.

烟酰胺核苷在体内变为称为NAD+的化学物质，对于维持适当的线粒体功能至关重要。研究人员发现，通过抑制线粒体呼吸，减少ATPSCKMT基因的表达，或通过增加烟酰胺核苷补充NAD+代谢物，可以绕过慢性疼痛。在另一组经历过炎症反应的小鼠中，接受烟酰胺核苷注射的队列显示出对疼痛刺激的反应较慢，这表明它们的超敏反应（慢性疼痛的标志）已受到调节。研究人员认为，进一步的研究可能会导致潜在的治疗方法，阻止慢性疼痛的发展，或逆转它。研究人员指出：“在我们的研究中，我们提供的证据表明，外周炎症会诱发感觉神经元持续的线粒体和代谢变化，从而影响神经元从随后的炎症触发引起的痛觉过敏中消退的能力。”。

“Importantly, targeting mitochondrial respiration, scavenging reactive oxygen species or supplementation with nicotinamide riboside (vitamin B3) both represent potential therapeutic strategies to restore failing pain resolution pathways, thereby treating chronic inflammatory pain.”The study was published in the journal C.

“重要的是，针对线粒体呼吸，清除活性氧或补充烟酰胺核苷（维生素B3）都是恢复失败的疼痛消退途径的潜在治疗策略，从而治疗慢性炎症性疼痛。”该研究发表在期刊C。