Organized trafficking of anandamide and related lipids

N-arachidonylethanolamide (anandamide or AEA) is an endogenous long-chain fatty acid ethanolamide with activity at both the cannabinoid 1 (CB(1)) and cannabinoid 2 (CB(2)) receptors, as well as the transient receptor potential vanilloid 1 (TRPV1) receptor. Whereas the mechanisms for both AEA biosynthesis and metabolism are fairly well established, the manner by which AEA is accumulated into cells remains controversial. The overwhelming majority of scientific reports indicate that this lipid neuromodulator is taken into cells via a facilitated process. Some reports have suggested that AEA uptake occurs by facilitated diffusion. Recent evidence indicates that AEA uptake may occur via endocytosis, contesting the premise that passive diffusion is the mechanism by which AEA transverses the plasma membrane. This chapter serves as an introduction to the endocannabinoid field with an emphasis on the various proposed mechanisms for the cellular uptake of endocannabinoids and other related hydrophobic molecules.