Arachidonoylethanolamide

Arachidonoylethanolamide, also known as N-arachidonoylethanolamine (AEA), is an endogenous lipid neurotransmitter that is part of the endocannabinoid system. It acts as a natural ligand for the cannabinoid receptors CB1 and CB2 and modulates synaptic signaling in the central nervous system and other tissues.

Chemically, AEA is an amide formed from arachidonic acid and ethanolamine; it is a long-chain fatty amide that is highly lipophilic and readily crosses cell membranes.

Biosynthesis occurs on demand from membrane phospholipids via N-acyl phosphatidylethanolamines and the enzyme NAPE-PLD. Its inactivation is primarily through hydrolysis by fatty acid amide hydrolase (FAAH), yielding arachidonic acid and ethanolamine. Uptake mechanisms for AEA are still debated and not fully understood.

AEA functions as a retrograde messenger in synapses, dampening neurotransmitter release and influencing processes such as pain perception, appetite, mood, learning, and memory. It also interacts with other targets, including TRPV1 receptors and peroxisome proliferator-activated receptors, and can be metabolized by cyclooxygenase-2 to prostamides, linking endocannabinoid signaling with inflammatory pathways.

Because of its role in modulating endocannabinoid tone, AEA has been investigated for analgesic and antiemetic properties. Inhibitors of FAAH elevate AEA levels and have been explored as potential analgesics, though clinical development has faced safety and efficacy considerations.