In recent years, lipids have come to the foreground as signaling mediators in the central nervous system (CNS) 1,2 . While classical neurotransmitters are stored in synaptic vesicles and released on fusion with the plasma membrane of neurons, due to their lipophilic nature, lipids readily diffuse through membranes and are not stored in vesicles. It is, therefore, generally accepted that signaling lipids are produced 'on demand' and are rapidly metabolized to terminate their biological action 3 . In particular, NAEs, including N-palmitoylethanolamine (PEA), N-oleoylethanolamine (OEA) and the endocannabinoid anandamide (N-arachidonoylethanolamine, AEA) have emerged as key lipid signaling molecules. Genetic deletion or pharmacological inhibition of the main NAE hydrolytic enzyme, fatty acid amide hydrolase (FAAH), revealed elevated anandamide, PEA and OEA levels in brain and implicated these molecules in the modulation of various physiological processes such as pain, stress, anxiety, appetite, cardiovascular function and inflammation [4][5][6][7] . The physiological effects resulting from perturbation of the production of anandamide and other NAEs in living systems are, however, poorly studied, partly because of a lack of pharmacological tools to modulate their biosynthetic enzymes 8 . NAPE-PLD is generally considered a principal NAE biosynthetic enzyme 9,10 . Biochemical and structural studies have demonstrated that NAPE-PLD is a membrane-associated, constitutively active zinc hydrolase with a metallo-β-lactamase fold 11 . The enzyme generates a broad range of NAEs by hydrolysis of the phosphodiester bond between the phosphoglyceride and the NAE in N-acylphosphatidylethanolamines (NAPEs) 12 . Knockout (KO) studies have shown that the Ca 2+ -dependent conversion of NAPE to NAEs bearing both saturated and polyunsaturated fatty acyl groups are fivefold reduced in brain lysates from mice that genetically lack Napepld 13 . In accordance, reduced levels of saturated and mono-unsaturated NAEs were observed in the brains of NAPE-PLD KO mice [13][14][15] . Anandamide levels were not reduced in the transgenic model reported by Leung et al., which suggested the presence of compensatory mechanisms 13 . Indeed, multiple alternative biosynthetic pathways for anandamide have been discovered since 10 .
