Pathophysiology
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,...