NAAA-regulated lipid signaling governs the transition from acute to chronic pain

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-alpha (PPAR-alpha). 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-alpha-dependent reprogramming of local core metabolism from aerobic glycolysis, which is transiently enhanced after end-organ damage, to mitochondria! respiration. The results identify NAAA as a crucial control node in the transition to chronic pain and a molecular target for diseasemodifying medicines.

Automated summary

Chronic pain affects a large population worldwide and understanding the molecular events behind it is crucial for the development of effective therapies. The study highlights NAAA as a key control point in chronic pain progression that can be targeted with small-molecule therapeutics. Inhibiting NAAA can trigger a shift in local metabolism from aerobic glycolysis to mitochondrial respiration, effectively halting chronic pain development.