Chronic pain is a leading cause of years lived in disability and impaired quality of life, yet treatment options are limited and often induce severe side effects. A new breakthrough offers the possibility of a different treatment option.
Scientists from the Centre for Translational Immunology at University Medical Centre Utrecht (the Netherlands) have identified that a transient inflammatory pain causes mitochondrial and redox changes in sensory neurons. These changes persist beyond pain resolution.
The changes appear to predispose to a failure in resolution of pain caused by a subsequent inflammation. It was also found that targeting the cellular redox balance prevents and treats chronic inflammatory pain in rodents. This has implications for the management of human pain.
Pain often persists in patients with an inflammatory disease, even after the inflammation has subsided. The molecular mechanisms leading to this failure in pain resolution and the transition from acute to chronic pain have, to date, been poorly understood.
Scientists have long-thought that mitochondrial dysfunction is involved. In a recent clinical study, approximately 70 percent of patients with heritable mitochondrial diseases develop chronic pain. However, the exact role of mitochondria in the resolution of inflammatory pain remained unclear.
To unravel the role of mitochondria in pain resolution, Hanneke Willemen in the research group lead by Niels Eijkelkamp used a model of hyperalgesic priming. In this model, a transient inflammation causes neuronal plasticity, which results in persistence of pain after a subsequent inflammatory stimulus.
The scientists identified that hyperalgesic priming in mice causes mitochondrial and metabolic disturbances in sensory neurons. The investigators associate these disturbances with an increase in the expression of a mitochondrial protein (ATPSc-KMT) which in a previous study has been linked to chronic pain in patients.
By using genetic and pharmacological approaches the researchers showed that inhibit mitochondrial respiration, ATPSCKMT expression and supplementation of one of the affected metabolites restores resolution of inflammatory pain and prevents chronic pain development.
In other words, it was found that 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.
In terms of the implications, 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, and for treating chronic inflammatory pain.
The findings have been published in the journal Cell Reports Medicine, titled “Inflammation-induced mitochondrial and metabolic disturbances in sensory neurons control the switch from acute to chronic pain.”
