Cannabinoid Receptors

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While we’ve talked at length about endocannabinoids, we haven’t really addressed where these little signaling molecules send their signals to...yet. Welcome to the world of endocannabinoid receptors!

By receptor, we’re referring to a cellular structure that ‘catches’ and processes signals; in this case neuro-transmitted signals. The endocannabinoid system possesses at least two different types of receptors: CB1, found mostly in the brain, and CB2, found mostly in the body. These receptors exist to pick up signals from both endo- and phytocannabinoids. In other words, they serve to complete a very important, very complex feedback loop.

Cannabinoid Receptors

Even more unique is the way that cannabinoid receptors are positioned to receive messages. They’re what’s called G-protein coupled receptors (GPCR’s), with a structure that’s woven back and forth across the surface of the cell. CB1 receptors are actually the most common GPCR in the human brain!

That’s not the unique part, though. The endocannabinoid system’s CB1 and CB2 receptors are actually the only GPCR’s to work through receiving retrograde signals.

Let’s start with the basics: think CB1 receptors in the brain, and CB2 in the body. But reality isn’t always so simple; as it turns out, both types of receptors are located all over. In addition, there may even be a third type of endocannabinoid receptor, which for now being called GPCR-119.

With all that said, CB1 receptors are found mostly in the brain. They’re located most densely in the hippocampus, cerebellum, and basal ganglia. That means they’re able to influence memory, emotion, and other aspects of advanced consciousness.

It’s largely because of CB1 that the endocannabinoid system has been described as “a literal bridge between body and mind”. Or, in the words of pioneering researcher professor Di Marzo: the ECS helps a person “eat, sleep, forget”. Let’s take a deeper look:

CB1 in the hippocampus: Many different endocannabinoids hit these receptors, which may gently regulate emotion, long-term potentiation, and the storage of memories.

Cannabinoid Receptors
Cannabinoid Receptors

CB1 in the cerebellum: Both endo- and phytocannabinoids may interact with CB1 receptors in the cerebellum, helping control voluntary movements and fostering optimal cellular signalling by boosting levels of other protein messengers like the arrestins.

The relaxing nature of cannabinoids is perhaps produced most directly within the cerebellum, where a multitude of other receptors work with CB1 to inhibit, or calm, neurotransmission via retrograde signalling.

CB1 in the basal ganglia: The basal ganglia is especially rich in cannabinoid receptors. They may help prevent motor neuron breakdown, and are likely to also play a role in other nervous system disorders. Also able to activate CB2 and even TRPV1 receptors, cannabinoids within the basal ganglia may work as neuroprotectants.

Cannabinoid Receptors
Cannabinoid Receptors

CB1 in the hypothalamus: These receptors play an important role in energy balance. When activated by cannabinoids, the hypothalamus is able to regulate production of leptin, ghrelin, adiponectin, and other hunger hormones. Increased thermogenesis from uncoupling proteins may occur, too.

The impact of cannabinoids on the hypothalamus may have downstream effects on the endocrine system, too. This means good things for one’s hormonal health. And while cannabinoids normally inhibit other neurons, like they do within the cerebellum, their action in this part of the brain actually stimulates the hypothalamic-pituitary-axis. With a strengthened HPA may come better ability to tolerate and respond to stress.

CB1 receptors aren’t only found in the brain. They’re also present along the spinal cord and throughout the peripheral nervous system.

While CB1 receptors are mostly in the brain, CB2 is present throughout the rest of the body. Their areas of greatest receptor concentration include white blood cells and organs like the spleen and tonsils. As you might suspect, CB2’s presence on white blood cells has important implications for immune health. Activate a CB2 receptor with an eCB like 2-AG and important inflammatory markers get regulated — usually lowered.

For example, cannabinoids have been shown to shift the conversion of lipid precursors away from inflammatory prostaglandins and cytokines and towards endocannabinoids. They also gently inhibit cyclooxygenases like COX-2. To move past technicalities and put things more simply, activation of CB2 receptors may calm and synchronize the immune system!

Cannabinoid Receptors

CB2 in the spleen: Think of the spleen as a filter for both red and white blood cells. With such importance, it’s no wonder that high levels of CB2 receptors are found there. Indeed, the CB2 receptor itself was first isolated and identified, way back in 1993, in rat spleen.

CB2 in the heart: CB2 is present in many parts of the heart, from its “smooth muscle” cells to cardiomyocytes. For these reason, it’s been of great interest to medical researchers: according to a 2012 study, “one can speculate that CB2 signaling is part of a protective response against human plaque vulnerability…” CB2 may also work alongside adenosine receptors to promote general heart health.

CB2 in the liver: There isn’t a high concentration of CB2 receptors in the liver — but the receptors that are there quickly up regulate during acute diseases. This may partially explain why certain cannabinoids impact liver enzymes so strongly.

CB2 in the gut: CB2 receptors can be found throughout the gut lining. CB2 is also found within the enteric nervous system, which connects the brain to the gut.

CB2 in muscle tissue: Interestingly enough, both CB1 and CB2 receptors can be found in most muscle tissue. They likely help control the flow of energy into the muscles, via regulating things like insulin sensitivity and calcium channels.

Don’t forget that calcium, as an electrolyte, is very important to hardworking muscles. Could it be that CB2 helps foster improvements in muscle firing and athletic performance? Only time will tell.

CB2 in fat tissue: Once thought to be an inert substance, it turns out that fat cells are pretty important. This is no truer than in the case of brown adipose tissue, or BAT. This type of fat cell helps regulate body temperature by burning other kinds of fat for fuel. If you’re wondering what makes brown fat, well, brown, it’s because of higher than normal concentrations of mitochondria:

CB2 in mitochondria: Even research pioneers were surprised when endocannabinoid receptors were discovered on the surfaces of mitochondria in 2012. Mitochondria, after all, generally have some genetic differences from the rest of the body — they even have their own DNA.

CB1 receptors aren’t only found in the brain. They’re also present along the spinal cord and throughout the peripheral nervous system.

While CB1 receptors are mostly in the brain, CB2 is present throughout the rest of the body. Their areas of greatest receptor concentration include white blood cells and organs like the spleen and tonsils. As you might suspect, CB2’s presence on white blood cells has important implications for immune health. Activate a CB2 receptor with an eCB like 2-AG and important inflammatory markers get regulated — usually lowered.

For example, cannabinoids have been shown to shift the conversion of lipid precursors away from inflammatory prostaglandins and cytokines and towards endocannabinoids. They also gently inhibit cyclooxygenases like COX-2. To move past technicalities and put things more simply, activation of CB2 receptors may calm and synchronize the immune system!

List of all known Cannabinoids in the human body What receptor do they affect (CB1 or CB2)? Can our body produce it? (tick list)
Anandamide CB1, GPCR-119 Yes
2-AG CB2 Yes
Arachidonoyl glycerol ether CB1 Yes
Noladin ether CB1 Yes
NADA CB1 Yes
OAE CB2 Yes
2-OG GPCR-119 Yes
CBD CB2 No
CBDa Indirect No
THC CB1 No
THCa Indirect No
CBC Indirect No
CBCa Indirect No
CBG CB2 No
CBGa Indirect No
CBN CB1 & CB2 No
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