Even though cannabis has been used for centuries, it wasn’t until the early 1990s that scientists discovered the endocannabinoid system (ECS). This discovery came after the identification, cloning, and characterization of the cannabinoid receptor 1 (CB1) found in the brain. Shortly after, a second receptor called CB2 was discovered, initially believed to be peripheral since it wasn’t found in the human brain.
The CB1 receptor is found on various types of cells in the central nervous system, but at different levels. While CB2 receptors are expressed at a lower level in brain neurons compared to CB1, they are moderately expressed in glial cells, including microglia, during degeneration and inflammation-related conditions. The ECS exists in almost all animals, from primitive invertebrates like sea urchins, nematodes, and mussels to more advanced mammals.
It consists of endocannabinoids (ECs), G protein-coupled receptors known as EC receptors (CB1 and CB2), and enzymes responsible for breaking down and recycling ECs. ECs are a diverse group of fatty acids that contain either an amide or ester group. They play a role in activating cannabinoid receptors to regulate brain function, immunity, and other physiological processes. This process exists in almost all animals, so it’s relation to other biological processes only differs by certain conditions.
The distribution of CB1 receptors varies among different species and can be found in both the central nervous system and the periphery. On the other hand, CB2 receptors are more abundant in cells of the intestinal and immune systems. These receptors are activated by endocannabinoids (ECs), which are released after synaptic transmission. The ECs then act on CB1 and CB2 receptors, leading to the inhibition of neurotransmitters that are responsible for various biological processes such as pain, inflammation, immunity, bone growth, and anxiety.
This modulation of neurotransmitters helps promote homeostasis and balance in the body. The two most extensively studied and potent ECs are anandamide and 2-arachidonoyl glycerol. Each EC has different affinities for CB1 and CB2 receptors. They are produced as needed by enzymes in the postsynaptic neuronal membranes and have a short half-life due to quick hydrolysis by enzymes such as fatty acid amide hydrolase and monoacylglycerol lipase.
In addition to their role in neurotransmission, ECs also play a critical role in modulating synaptic transmission. While early evidence suggested that ECs primarily function in retrograde synaptic signaling, recent studies have shown that they can also signal in a nonretrograde manner. It’s quite complicated, but we’ll delve deeper in the next post.