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.

NAAA-regulated lipid signaling governs the transition from acute to chronic pain / Fotio, Y.; Jung, K. -M.; Palese, F.; Obenaus, A.; Tagne, A. M.; Lin, L.; Rashid, T. I.; Pacheco, R.; Jullienne, A.; Ramirez, J.; Mor, M.; Spadoni, G.; Jang, C.; Hohmann, A. G.; Piomelli, D.. - In: SCIENCE ADVANCES. - ISSN 2375-2548. - 7:43(2021). [10.1126/sciadv.abi8834]

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

Mor M.;Piomelli D.
2021-01-01

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.
2021
NAAA-regulated lipid signaling governs the transition from acute to chronic pain / Fotio, Y.; Jung, K. -M.; Palese, F.; Obenaus, A.; Tagne, A. M.; Lin, L.; Rashid, T. I.; Pacheco, R.; Jullienne, A.; Ramirez, J.; Mor, M.; Spadoni, G.; Jang, C.; Hohmann, A. G.; Piomelli, D.. - In: SCIENCE ADVANCES. - ISSN 2375-2548. - 7:43(2021). [10.1126/sciadv.abi8834]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2932291
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