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. 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. It’s particularly prevalent in people with inflammatory and mitochondrial diseases.
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. 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. “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 Cell Reports Medicine.
