Given that cannabis (marijuana, hashish, ganja, dagga, etc.) is the most widely used illicit substance in the Western world, it behooves us as physicians to understand as much about it as possible. The cannabinoid receptor is a good starting point in such a pursuit.
Marijuana is not a single substance, but a collection of substances or compounds which become 2,000 on pyrolysis. Numbered among the 400 constituents of the plant Cannabis sativa are some 60 cannabinoids, the best-known of which are delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) (Figure) The first of these is psychoactive and is mainly responsible for the "high" its users experience. CBD is a precursor of THC, and CBN is a spin-off product.
The psychoactive constituents of cannabis produce their pharmacological effects by working at specific receptor sites in the brain that were first identified as such in 1988. Opioid receptors had been identified 15 years earlier, but the existence of cannabinoid receptors was not suggested by that discovery.
The Receptor System
It was its enantioselectivity for many of THC's effects that suggested a specific cannabinoid receptor. The naturally occurring (-)-enantiomer (either of a pair of molecules that are mirror images of each other) of trans-delta-9-THC was noted to have up to 100 times more potency than the (+)-enantiomer (Martin).
High degrees of enantioselectivity point to a specific mechanism of action, usually involving a receptor. Cannabinoids had already been shown to inhibit adenylate cyclase by interaction with a G1 protein (G proteins are so named because they bind to the nucleotides guanosine diphosphate [GDP] and guanosine triphosphate [GTP]. They are cell-signaling transducers [energy converters]; G proteins help cells in the body communicate with each other). The demonstration of such an associated second messenger system is important when it comes to proving that a binding site is actually a receptor. That the second messenger system most common for neurotransmitters in the brain is inhibited by cannabinoids strengthened the case for an endogenous cannabinoid system.
Autoradiography using labeled congeners demonstrated high concentrations of cannabinoid receptors in the substantia nigra, hippocampus and cerebellum. Appreciable concentrations were also found in the cerebral cortex. Most of the brainstem and pons contain low or minute concentrations. Several researchers have observed that the distribution of cannabinoid receptors in the brain is similar to that of dopamine D1 receptors, suggesting that the cannabinoid receptor system may function indirectly to modulate brain dopaminergic activity. The significance of this is discussed later.
On the heels of uncovering the cannabinoid receptor system came the discovery of an endogenous ligand (usually a small molecule that binds to a receptor) for the cannabinoid receptor in the brain. And here is where our story really begins.
The recognition of the opioid receptor in 1973 led to curiosity as to why the human brain (as well as nerves in the intestine) would have specific receptors for a substance, morphine, which the opium poppy plant produces as a nitrogenous waste product. When the endogenous "opioids" were found, they turned out not to be opiate-like structurally but instead to be peptides. Thus, it can be said that morphine and related opiates merely mimic the actions of endogenous "opioid" peptides at their receptor sites.
An analogous situation exists with the cannabinoids. The natural ligand has been found to be anandamide, structurally unrelated to cannabinoids. Anandamide is the arachidonoyl amide of ethanolamine (Devane and others).
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