Scientists from the Center for Translational Immunology at University Medical Center Utrecht in the Netherlands have discovered that a brief episode of inflammatory pain induces enduring mitochondrial and redox alterations in sensory neurons, persisting beyond the resolution of pain. These changes seem to make individuals more susceptible to a failure in pain resolution triggered by subsequent inflammation. Moreover, the researchers found that manipulating cellular redox balance can prevent and treat chronic inflammatory pain in rodents.

In patients with inflammatory diseases, pain often lingers even after the inflammation has diminished. The precise molecular mechanisms leading to this failure in pain resolution and the shift from acute to chronic pain remain unclear. There have been indications that mitochondrial dysfunction might play a role. Approximately 70 percent of patients with heritable mitochondrial diseases experience chronic pain, according to a clinical study. Nevertheless, the specific involvement of mitochondria in resolving inflammatory pain has been uncertain.

To delve into the role of mitochondria in pain resolution, Dr. Hanneke Willemen, part of the research group led by Dr. Niels Eijkelkamp at the Center for Translational Immunology, UMC Utrecht, employed a hyperalgesic priming model. In this model, a brief inflammation induces neuronal plasticity, leading to persistent pain after a subsequent inflammatory stimulus—an ideal model for studying the breakdown in pain resolution. The researchers found that hyperalgesic priming in mice causes mitochondrial and metabolic disturbances in sensory neurons, linked to an increase in the expression of a mitochondrial protein (ATPSc-KMT) previously associated with chronic pain in patients. Through genetic and pharmacological interventions, they demonstrated that inhibiting mitochondrial respiration, suppressing ATPSCKMT expression, and supplementing one of the affected metabolites can restore the resolution of inflammatory pain and prevent the development of chronic pain. The results of this collaborative study, which involved researchers from the University of Oslo in Norway, have been published in Cell Reports Medicine.

Dr. Hanneke Willemen concludes that their study provides evidence that peripheral inflammation induces lasting mitochondrial and metabolic changes in sensory neurons, impacting the neurons’ ability to recover from hyperalgesia triggered by subsequent inflammatory stimuli. The metabolic alterations in sensory neurons contribute to the failure of endogenous pain resolution pathways, driving the transition to chronic pain. Significantly, targeting mitochondrial respiration, scavenging reactive oxygen species, or supplementing with nicotinamide riboside (vitamin B3) could potentially serve as therapeutic strategies to reinstate failing pain resolution pathways and treat chronic inflammatory pain.

Chronic pain poses a significant burden on quality of life, and available treatments often come with severe side effects. The conventional belief is that pain resolution occurs when the factors causing pain dissipate. However, a considerable percentage of rheumatic arthritis patients experience persistent pain despite minimal joint inflammation or even remission. Growing evidence suggests that pain resolution after tissue damage or inflammation is not a passive process but an active one involving endogenous pain resolution mechanisms. Understanding the molecular mechanisms contributing to the failure in pain resolution is an ongoing challenge, but this study addresses part of that gap and proposes a potential therapeutic approach to promote pain resolution.


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