Neuroimmune-glial cells interactions elevate the kynurenine metabolic pathway to sustain neuropathic pain

Neuropathic pain is triggered by injury to the somatosensory system, and is one of the most important types of chronic pain. Nevertheless, critical pathophysiological mechanisms that maintain neuropathic pain are poorly understood. Here, we show that neuropathic pain is abrogated when the kynurenine metabolic pathway (KYNPATH) initiated by the enzyme indoleamine 2,3-dioxygenase (IDO) is ablated pharmacologically or genetically. Mechanistically, it was found that IDO upregulation in dendritic cells that accumulate in the dorsal root leptomeninges led to increased levels of kynurenine (Kyn) in the spinal cord, where Kyn is metabolized by astrocytes-expressed kynurenine-3-monooxygenase into a pro-nociceptive metabolite 3-hydroxykynurenine. Ultimately, 3-hydroxyanthranilate 3,4-dioxygenase-derived quinolinic acid, the final step of the canonical KYNPATH, is also involved in neuropathic pain development through the activation of glutamatergic NMDA receptor. In conclusion, these data reveal a novel role for KYNPATH as an important factor maintaining neuropathic pain during neuroimmune-glia cell interactions. This novel paradigm offers potential new targets for drug development against this type of chronic pain.