Proposed mechanism of pain inhibition by N-acylethanolamine acid amidase
(NAAA). Panel A: key enzymatic pathways for fatty acid ethanolamide synthesis
and degradation (solid black arrows), and a proposed mechanism of pain
inhibition involving palmitoylethanolamide (PEA) activation of PPARα
(blue arrows), and PPARα-mediated pain inhibition (green arrows). Panel
B: Injury-induced inhibition of the enzyme that synthesizes PEA
(N-acyl-phosphatidylethanolamine phospholipase D, NAPE-PLD) and ensuing loss of
PEA-PPARα antihyperalgesia. Panel C: Inhibition of N-acylethanolamine
acid amidase (NAAA) with the novel compound ARN077 raises PEA concentrations,
thus reinstating PPARα antihyperalgesia.
PE, phosphatidylethanolamine. PC, phosphatidylcholine. NAT,
N-acetyltransferase. NAPE, N-acylphosphatidylethanolamines. AEA,
arachidonoylethanolamide (anandamide). OEA, oleoylethanolamide. AA, arachidonic
acid. OA, oleic acid. PA, palmitic acid. EA, ethanolamine.