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bioRxiv · 10.1101/2022.08.29.505682

Inflammation-induced mitochondrial and metabolic disturbances in sensory neurons control the switch from acute to chronic pain

Willemen, H.·Ribeiro, P.·Broeks, M.·Meijer, N.·Versteeg, S.·Malecki, J.·Falnes, P.·Jans, J.·Eijkelkamp, N.
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Abstract

Pain often persists in patients with inflammatory diseases, even when the inflammation has subsided. The molecular mechanisms leading to this failure in resolution of inflammatory pain and the transition to chronic pain are poorly understood. Mitochondrial dysfunction in sensory neurons has been linked to chronic pain, but its role in resolution of inflammatory pain is unclear. Transient inflammation causes neuronal plasticity, called hyperalgesic priming, which impairs resolution of hyperalgesia induced by a subsequent inflammatory stimulus. We identified that hyperalgesic priming in mice caused disturbances in mitochondrial respiration, oxidative stress, and redox balance in dorsal root ganglia (DRG) neurons. Preventing these priming-induced disturbances restored resolution of inflammatory hyperalgesia. Concurrent with these mitochondrial and metabolic changes, the expression of ATPSc-KMT, a mitochondrial methyltransferase, was increased in DRG neurons in primed mice. ATPSc-KMT overexpression in DRG neurons of naive mice induced similar mitochondrial and metabolic changes as observed after priming, leading to failure in pain resolution. Inhibition of mitochondrial respiration, knockdown of ATPSCKMT expression, or NAD+ supplementation were sufficient to restore resolution of inflammatory pain and prevent chronic pain development. Thus, inflammation-induced mitochondrial-dependent disturbances in DRG neurons promote failure in inflammatory pain resolution and drive the transition to chronic pain.

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Willemen, H., Ribeiro, P., Broeks, M., Meijer, N., Versteeg, S., Malecki, J., Falnes, P., Jans, J., Eijkelkamp, N.. 2022-08-29. Inflammation-induced mitochondrial and metabolic disturbances in sensory neurons control the switch from acute to chronic pain. https://doi.org/10.1101/2022.08.29.505682

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