Search

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.

SummaryThe current paradigm is that inflammatory pain passively resolves following the cessation of inflammation. Yet, in a substantial proportion of patients with inflammatory diseases, resolution of inflammation is not sufficient to resolve pain, resulting in chronic pain. Mechanistic insight how inflammatory pain is resolved is lacking. Here we show that macrophages actively control resolution of inflammatory pain remotely from the site of inflammation by transferring mitochondria to sensory neurons. During resolution of inflammatory pain in mice, M2-like macrophages infiltrate the dorsal root ganglia that contain the somata of sensory neurons, concurrent with the recovery of oxidative phosphorylation in sensory neurons. The resolution of pain and the transfer of mitochondria requires expression of CD200 Receptor (CD200R) on macrophages and the non-canonical CD200R-ligand iSec1 on sensory neurons. Our data reveal a novel mechanism for active resolution of inflammatory pain.Graphical Abstract