____________________________________________________ Medical Marijuana and Other Cannabinoids
CB2 Receptors CB2 receptors are sparsely expressed in the central nervous system (CNS) but highly expressed in immune cells, where they play an important role in regulating immune function and inflammation. Their activation modulates immune cell migration and cytokine and chemokine release, and CB2 recep- tor expression on CNS microglia may explain cannabinoid efficacy in reducing cytokine-mediated neuroinflammation [30; 41; 42; 43]. Other Endocannabinoid Receptors In addition to CB1 and CB2 receptors, endocannabinoids are thought to bind several other molecular targets. These include a third presumed cannabinoid receptor, GPR55 (sometimes termed CB3), the transient receptor potential cation chan- nel subfamily V member 1 (TRPV1), and a class of nuclear receptors/transcription factors known as the peroxisome proliferator-activated receptors (PPARs) [30]. Endogenous Cannabinoids Receptor Ligands Anandamide and 2-arachidonoyl glycerol (2-AG) are the two primary endogenous cannabinoid receptor ligands. Anandamide (Arachidonoyl Ethanolamide, AEA) Anandamide was the first endogenous cannabinoid identi- fied by researchers and was assigned its name after ananda , the Sanskrit word for “bliss” [37]. Anandamide is derived from arachidonic acid following synthesis from membrane phospholipid precursors. At CB receptors, anandamide acts as a partial agonist, with slightly higher binding affinity at CB1 versus CB2 [36]. Anandamide is hydrolysed by the enzyme fatty-acid amide hydrolase (FAAH) as the primary metabolic pathway [44]. 2-Arachidonoyl Glycerol (2-AG) 2-AG binds essentially equally to both CB receptors (with slightly higher CB1 affinity) and possesses greater overall potency and efficacy than anandamide at both CB receptors [36]. 2-AG is an arachidonic acid derivative synthesized by the same process as anandamide. The metabolic pathway of 2-AG predominantly involves monoacylglycerol lipase (MGL or MAGL) [36; 44]. Additional Endocannabinoids Other endogenous molecules have been identified that mimic endocannabinoid effects. These include 2-AG ether (noladin ether), N -arachidonoyl dopamine (NADA), virod- hamine, N -homo- γ -linolenoylethanolamine (HEA), and N -docosatetraenoylethanolamine. Although the molecules palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) bind to PPARs instead of cannabinoid receptors, their action potentiates anandamide effect by inhibiting FAAH (the enzyme that degrades anandamide) and by direct allosteric effects on
other receptors. The sum of these effects is referred to as the “entourage effect” [45; 46; 47; 48]. Advocates of the term sug- gest the effect mechanism is the underlying reason that many patients claim to experience an overall better effect from full- spectrum Cannabis products. However, this suggestion relies mostly on anecdotal evidence from observational studies. Crit- ics state that the “entourage effect” is unsupported by sound evidence and that the term is primarily used for marketing purposes in the cannabis industry [49; 50; 51; 52]. PEA has become a research focus, with a growing number of clinical trials evaluating its pain-reducing efficacy in diverse chronic pain conditions [53; 54]. MECHANISMS OF ECS ACTION Cannabinoid binding and activation of CB1/CB2 receptors produce many pharmacologic effects resulting from ECS modulation of other neurotransmitter systems [55]. Shared CB Mechanisms The ECS facilitates rapid local response to pathologic states or disease. Increased intracellular calcium release from neuronal activation or cellular stress triggers membrane phospholipids to synthesize and immediately release anandamide or 2-AG, which binds and activates nearby CB receptors. This activation inhibits adenylyl cyclase activity, decreasing cyclic adenosine monophosphate (AMP) formation and protein kinase A activ- ity, which in turn blocks Ca2+ influx through various calcium channels. CB receptor activation also stimulates inwardly rectifying potassium (K+) channels and the mitogen-activated protein kinase signaling cascades. Cellular uptake and enzy- matic degradation rapidly clear the endocannabinoids [56]. The ECS alters CB1 or CB2 receptor expression during stress response, which is beneficial in some pathologic states (e.g., neuropathic pain, multiple sclerosis) because increased CB expression may curtail symptoms or disease progression and provide a protective role. Alteration in CB1 expression is maladaptive in other disease conditions, such as CB1 up- regulation in liver fibrosis and down-regulation in colorectal cancer [56; 57; 58]. CB1 Mechanisms In CNS tissue, CB1 activation inhibits neuronal calcium channels and activates potassium channels, as described. Anandamide and 2-AG are synthesized and released from post-synaptic neuron terminals, travel “backwards” across the synaptic cleft to presynaptic neurons, and bind CB1 receptors on pre-synaptic terminals. This, in turn, inhibits release from excitatory and inhibitory synapses of serotonin, glutamate, ace- tylcholine, gamma-aminobutyric acid (GABA), noradrenaline, dopamine, D-aspartate, and cholecystokinin. This process of post-synaptic release, backwards diffusion across the synaptic cleft, and pre-synaptic CB1 binding is termed “retrograde signaling” [36; 59; 60].
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