*2.1. Endocannabinoids*

EC are a class of arachidonic acid (AA) derivatives that interact with CB and were originally described as targets of Δ9-Tetrahydrocannabinol (THC), the main psychoactive constituent of *Cannabis sativa* [29]. EC share a common backbone structure resulting from their synthesis from membrane phospholipid precursors that contain AA and are conjugated either with ethanolamine or glycerol [22,26,30]. They are synthetized on demand, often in response to increased intracellular calcium concentrations [31]. EC amount is tightly regulated by changes in its catabolism rather by their synthesis. Figure 1 depicts the chemical structure of the main EC. Other less-characterized CB-interacting peptides and a series of AA derivatives that generate endocannabinoid-like effects such as N-palmitoylethanolamine (PEA) and Oleoylethanolamine (OEA) have also been described [32]. Most investigations focus on the first discovered and best studied EC: N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) [33,34].

**Figure 1.** Chemical structures of endogenous cannabinoids: *N*-arachidonoylethanolamine (AEA, anandamide), 2-arachidonoylglycerol (2-AG), *O*-arachidonoyl-ethanolamine (*O*-AEA, virodhamine), *N*-arachidonoyl dopamine (NADA), and 2-arachidonyl-glyceryl ether (2-AGE, noladin ether).

AEA is a *N*-(polyunsaturated fatty acyl) generated from *N*-arachidonoyl phosphatidylethanolamine (NAPE) through multiple different pathways: cleavage by phospholipase D (PLD), sequential deacylation of NAPE by α,β-hydrolase followed by the cleavage of glycerophosphate, and phospholipase C-mediated hydrolysis of NAPE, which is then dephosphorylated by phosphatases [35]. It is a partial agonist of CB1 and CB2, presenting a lower intrinsic activity for the latter [29]. Fatty acid amino hydrolase (FAAH) is the main enzyme responsible for AEA degradation. However, it can also be catabolized via oxidation by cyclooxygenase-2 (COX-2) and by N-acylethanolamine-hydrolysing acid amidase (NAAA) [31]. 2-AG is an ester formed from AA-containing phospholipids and glycerol [31] via three major pathways: sequential activation of a phospholipase Cβ and a diacylglycerol lipase, sequential action of phospholipase A1 and a lyso phospholipase C, and by dephosphorylation of arachidonoyl- lysophosphatidic acid [36–38]. 2-AG is a full agonist of both CB receptors with moderate-to-low affinity [32]. Monoacylglycerol lipase (MAGL) is its principal degradation enzyme. 2-AG is also degraded by alpha/beta domain hydrolases 6 and 12 (ABHD6 and 12), oxidized by COX-2 and hydrolysed under some conditions by FAAH [31]. Although AEA and 2-AG are involved in similar processes such as the control of redox homeostasis and display anti-inflammatory effects, both agents are implicated in a myriad of different activities. For instance, AEA participates in cell cycle regulation and apoptosis, whereas 2-AG is important in synaptic signalling.
