Clinical meaning
The endocannabinoid system (ECS) is a ubiquitous lipid-based neuromodulatory system involved in homeostatic regulation of pain, mood, appetite, immune function, and memory. It comprises three core components: endocannabinoid ligands, cannabinoid receptors, and metabolic enzymes.
Endocannabinoid ligands are arachidonic acid derivatives synthesized on demand from membrane phospholipids (not stored in vesicles). Anandamide (AEA, arachidonoylethanolamide) is a partial agonist at CB1 and weak agonist at CB2, synthesized by N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) and degraded by fatty acid amide hydrolase (FAAH). 2-Arachidonoylglycerol (2-AG) is a full agonist at both CB1 and CB2, synthesized by diacylglycerol lipase (DAGL) and degraded by monoacylglycerol lipase (MAGL). Retrograde signaling is the primary mode: postsynaptic neurons synthesize endocannabinoids that travel backward across the synapse to bind presynaptic CB1 receptors, inhibiting neurotransmitter release.
CB1 receptors are G-protein coupled receptors (Gi/o) predominantly expressed in the central nervous system: cortex, hippocampus, basal ganglia, cerebellum, hypothalamus, and periaqueductal gray. CB1 activation inhibits adenylate cyclase (reducing cAMP), activates inwardly rectifying potassium channels (hyperpolarization), and inhibits voltage-gated calcium channels (reducing neurotransmitter release). CB1 mediates the psychoactive effects of THC, modulates pain perception, appetite, memory consolidation, and motor coordination.
CB2 receptors are primarily expressed on immune cells (macrophages, B cells, T cells, microglia) and peripheral tissues (spleen, tonsils, bone). CB2 activation modulates cytokine release, immune cell migration, and inflammatory cascades. CB2 does not produce psychoactive effects. CB2 agonists are being investigated for anti-inflammatory and neuroprotective applications.