Figure 3. Formation and deactivation of endocannabinoid lipids.

(A) Anandamide is generated by hydrolysis of the membrane lipid, N-arachidonoyl-phosphatidylethanolamine (NArPE), which is catalyzed in neurons by a phospholipase D that selectively recognizes N-acylated species of PE (NAPE-PLD). The concentrations of NArPE and anandamide are very low in resting neurons, but quickly increase in response to neural activity and/or neurotransmitter receptor occupation. In macrophages, activation of Toll-like receptor 4 (TLR4) by the bacterial endotoxin lipopolysaccharide stimulates an as-yet-uncharacterized phospholipase C (PLC), which converts NArPE into phospho-anandamide. This intermediate is dephosphorylated by a phosphatase (P-ase) to form anandamide. Endogenously produced anandamide modulates nociception by binding to CB₁ cannabinoid receptors. In both neurons and macrophages, anandamide is converted into arachidonic acid and ethanolamine by fatty acid amide hydrolase (FAAH), which is selectively blocked by inhibitors such as the O-arylcarbamate derivative, URB597. Anandamide can also be transformed by cyclooxygenase-2 (Cox-2) into proalgesic prostamides, a reaction that is prevented by substrate-selective inhibitors such as LM-4131. Non-steroidal anti-inflammatory drugs (NSAIDs) stop the conversion of arachidonic acid into prostaglandins by inhibiting both Cox-1 and Cox-2 activities.

(B) 2-arachidonyl-sn-glycerol (2-AG). G_q-coupled receptors and Toll-like receptor-4 (TLR4) stimulate phospholipase C-β (PLC-β), which converts phosphatidylinositol-4,5-bisphosphate (PIP₂) into 1,2-diacylglycerol (DAG). DAG is hydrolyzed by diacylglycerol lipase-α (DGL-α) to yield 2-AG, which inhibits nociceptive responses by activating CB₁ and CB₂ cannabinoid receptors. Monoacylglycerol lipase (MGL) terminates 2-AG signaling by hydrolyzing this glycerol ester into arachidonic acid and glycerol. 2-AG and arachidonic acid may be transformed by cyclooxygenase (Cox-1) and/or Cox-2 into various families of proalgesic lipid mediators, which include PGE₂ glycerol ester (derived from 2-AG) and PGE₂ (derived from arachidonic acid).