Author:
Maganin Alexandre G.,Souza Guilherme R.,Fonseca Miriam D.,Lopes Alexandre H.,Guimarães Rafaela M.,Dagostin André,Cecilio Nerry T.,Mendes Atlante S.,Gomes Francisco I.,Marques Lucas M.,Silva Rangel L,Arruda Leticia M.,Santana Denis A.,Lemos Henrique,Huang Lei,Davoli-Ferreira Marcela,Coelho Danielle S.,Sant’anna Morena B.,Kusuda Ricardo,Talbot Jhimmy,Pacholczyk Gabriela,Buqui Gabriela A.,Lopes Norberto P.,Alves-Filho Jose C.,Leão Ricardo,O’Connor Jason C.,Cunha Fernando Q.,Mellor Andrew,Cunha Thiago M.
Abstract
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. In conclusion, these data reveal a novel role for KYNPATH as an important factor maintaining neuropathic pain during neuroimmune-glia cells interactions. This novel paradigm offers potential new targets for drug development against this type of chronic pain.
Publisher
Cold Spring Harbor Laboratory