I am a
Home I AM A Search Login

Papers of the Week

Papers: 8 Oct 2022 - 14 Oct 2022

Animal Studies, Pharmacology/Drug Development

2022 Oct 13

J Clin Invest

Editor's Pick

Meningeal dendritic cells drive neuropathic pain through elevation of the kynurenine metabolic pathway in mice.


Maganin A G, Souza GR, Fonseca MD, Lopes AH, Mano Guimarães RM, Dagostin A, Cecilio NT, Mendes AS, Gonçalves WA, Silva C E, Fernandes Gomes FI, Mauriz Marques LM, Silva RL, Arruda LM, Santana DA, Lemos H, Huang L, Davoli-Ferreira M, Santana-Coelho DS, Sant'Anna MB, et al.
J Clin Invest. 2022 Oct 13.
PMID: 36227694.


Neuropathic pain is one of the most important clinical consequences of injury to the somatosensory system. Nevertheless, the critical pathophysiological mechanisms involved in neuropathic pain development are poorly understood. In this study, we found that neuropathic pain is abrogated when the kynurenine metabolic pathway initiated by the enzyme indoleamine 2,3-dioxygenase (IDO1) is ablated pharmacologically or genetically. Mechanistically, it was found that IDO1-expressing dendritic cells (DCs) accumulated in the dorsal root leptomeninges and led to an increase in kynurenine levels in the spinal cord. In the spinal cord, kynurenine was metabolized by kynurenine-3-monooxygenase-expressing astrocytes into a pro-nociceptive metabolite 3-hydroxykynurenine. Ultimately, 3-hydroxyanthranilate 3,4-dioxygenase-derived quinolinic acid formed in the final step of the canonical KYNPATH was also involved in neuropathic pain development through the activation of the glutamatergic N-methyl-D-aspartate (NMDA) receptor. In conclusion, these data revealed a novel role for DCs driving neuropathic pain development through elevation of the kynurenine metabolic pathway. This novel paradigm offers potential new targets for drug development against this type of chronic pain.