The endogenous ligands for cannabinoid receptors are the arachidonate derived lipophilic molecules N-arachidonylethanolamine (anandamide; AEA (Devane et al., 1992)) and 2-arachidonylglycerol (2-AG (Sugiura et al., 1995)). Both AEA and 2-AG do not behave as typical neurotransmitters. It is currently believed that both AEA and 2-AG are formed post-synaptically by activity-dependent cleavage of phospholipids' head groups by activation of specific enzymes, although activity-independent mechanisms of endocannabinoid synthesis have also been demonstrated. The biosynthesis of 2-AG is mediated by generation of diacylglycerol, via the actions of either phospholipase C (PLC) or phospholipase D (PLD), which is subsequently converted to 2-AG via the actions of DAG lipase (Hillard, 2000; Sugiura and Waku, 2002). The pathways mediating AEA synthesis are less well understood. To date, three distinct and independent mechanisms have been found to generate AEA (Liu et al., 2006; Okamoto et al., 2004; Simon and Cravatt, 2006); however, the pathway that is primarily responsible for neuronal AEA synthesis is not currently known (see (Ahn et al., 2008; Bisogno, 2008)) for details on putative biosynthetic pathways of AEA)
