Abstract |
Chronic pain affects 1.5 billion people worldwide but remains woefully undertreated. Understanding the molecular events leading to its emergence is necessary to discover disease-modifying therapies. Here we show that N-acylethanolamine acid amidase (NAAA) is a critical control point in the progression to pain chronicity, which can be effectively targeted by small-molecule therapeutics that inhibit this enzyme. NAAA catalyzes the deactivating hydrolysis of palmitoylethanolamide, a lipid-derived agonist of the transcriptional regulator of cellular metabolism, peroxisome proliferator-activated receptor-α ( PPAR-α). Our results show that disabling NAAA in spinal cord during a 72-h time window following peripheral tissue injury halts chronic pain development in male and female mice by triggering a PPAR-α-dependent reprogramming of local core metabolism from aerobic glycolysis, which is transiently enhanced after end-organ damage, to mitochondrial respiration. The results identify NAAA as a crucial control node in the transition to chronic pain and a molecular target for disease-modifying medicines.
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Authors | Yannick Fotio, Kwang-Mook Jung, Francesca Palese, Andre Obenaus, Alex Mabou Tagne, Lin Lin, Tarif Ibne Rashid, Romario Pacheco, Amandine Jullienne, Jade Ramirez, Marco Mor, Gilberto Spadoni, Cholsoon Jang, Andrea G Hohmann, Daniele Piomelli |
Journal | Science advances
(Sci Adv)
Vol. 7
Issue 43
Pg. eabi8834
(Oct 22 2021)
ISSN: 2375-2548 [Electronic] United States |
PMID | 34678057
(Publication Type: Journal Article)
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