Endocannabinoid

Endocannabinoids are endogenous lipid-based signaling molecules that bind to and activate cannabinoid receptors. The two best characterized endocannabinoids are anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG). They are synthesized on demand in response to neuronal activity and are not stored in synaptic vesicles. Endocannabinoids typically function in retrograde signaling: a postsynaptic neuron releases these lipids, which travel to presynaptic terminals to activate cannabinoid receptors and modulate the release of neurotransmitters such as GABA and glutamate, thereby influencing synaptic transmission and plasticity.

The central receptors for endocannabinoids are the CB1 receptor, abundant in the brain and nervous system, and the CB2 receptor, primarily found in immune cells and peripheral tissues. Activation of CB1 and CB2 modulates processes including pain sensation, appetite, mood, memory, stress response, and inflammatory function. Some endocannabinoid actions can involve other receptors or ion channels, such as GPR55 and TRPV1, but CB1 and CB2 are the primary mediators of classical endocannabinoid signaling.

Biosynthesis and termination involve specific enzymes. 2-AG is produced mainly by diacylglycerol lipase (DAGL), while AEA is produced via NAPE-PLD. Signal termination occurs mainly through enzymatic hydrolysis: FAAH degrades AEA and related N-acylethanolamines, whereas MAGL degrades 2-AG.

Endocannabinoid signaling plays a role in numerous physiological and pathological contexts, including analgesia, energy balance, mood regulation, inflammatory responses, and neuroprotection. Pharmacological interest includes inhibitors of FAAH and MAGL, as well as therapeutic use of cannabinoid compounds, though clinical applications must balance benefits with potential adverse effects.