CB2 receptors are the most mysterious of the components of the known endocannabinoid system, but figuring out exactly how they work could lead to revolutionary new treatments for autoimmune disease and other inflammatory disorders.

The endocannabinoid system is the system of neurotransmitters and receptors in the nervous system which is affected by cannabis. It regulates all sorts of functions, including mood, appetite, sleep, stress response, immune response — it has a hand in all the things that keep us in balance or “homeostasis” day-to-day.

The CB2 receptor is coded in your DNA by the CNR2 gene. CB2 “may function in inflammatory response, nociceptive transmission and bone homeostasis,” according to the GeneCards.org summary. The sparse description doesn’t reflect a niche function on CB2, but rather the lack of concrete data about the mysterious receptor.

This image is a model of the CB2 receptor based on experimental data. The red portion is a binding agent used in experimentation to suss out where the binding sites on the receptor are. Image courtesy of the Journal of Chemical Information and Modeling.

Both of the known endocannabinoid receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) are located on nerve cells throughout the body, but they have specific areas of concentration. CB1 receptors tend to concentrate around the brain and gut, while CB2 receptors seem concentrated in the brain and limbs, and to a lesser degree, the site of healing injuries.  Furthermore, CB2 receptors seem to be concentrated in tissues related to the immune system. 

Scientists theorize this part of the endocannabinoid system modulates immune response and inflammation on a cellular level. And inflammation is the real cause of symptoms of almost any disease — your nose runs not because the virus has set up its own waterworks in your sinuses, it’s your own body sending lymph, extra blood flow and mucous to the site of infection in an attempt to eject the virus.

When dealing with pathogens and infections, the inflammatory response is often helpful — all that mucous helps flush the viruses out of your sinuses. But in the case of autoimmune disease or nerve pain, the inflammatory response has gone haywire and your body is attacking itself for no external reason, or a benign one (think of the allergic response to otherwise harmless pollen).

CB2 receptors modulate the immune response
The inflammatory response is a reaction to an external threat entering the body (e.g. a wound). CB2 receptors are critical for this response.

This is where scientists hope to make big strides with the CB2 receptor as a target for pharmaceuticals, including cannabis and cannabis distillates.

CB2 receptors are now the toughest part of the endocannabinoid system to study because their activation and effects are much more subtle that those of the CB1 receptor. Also, CB2 receptors don’t have just one ligand, or connecting neurotransmitter; CB2 can accept lots of different neurotransmitters that each activate it slightly differently and cause different effects.

As a result, it’s harder to design straightforward experiments that will give you worthwhile data on CB2 signaling.

Ion channel regulation by CB2 receptors

The CB2 receptors also appear to regulate the voltage of nerve cells by controlling calcium ion channels in the cell membrane.

The electrical charge of a neuron is dependent on the different concentrations of potassium, sodium, and calcium inside and outside of the cell — kind of like a battery that has one chamber full of a positively charged acid and the other full of a negatively charged base. These substances exist as ions, meaning they are positively or negatively charged. Your nervous system can change the voltage of its cells by manipulating concentrations of these ions through ion channels.

Ion channels are openings on the cell membrane through which protein carriers shuttle different ions in and out of the cell to regulate its electrical charge. This gradient of different ion concentrations inside and outside of the cell gives neurons their electrical properties and CB2 receptors, when bound with the right neurotransmitters, help to regulate this influx/efflux of ions, regulating neuronal firing and voltage levels.

Functional selectivity of CB2 signaling

CB2 receptors also may couple with a range of neurotransmitters that also activate other pathways in other nerve signaling systems. Whereas the main ligand for CB2 is 2-AG, it’s not the only one. Ligands are the transmitters that fits in the receptor, similar to a key in a lock. Different neurotransmitters from other systems may also activate CB2 receptors to varying degrees, sometimes forcing them inside the cell membrane after activation in a process called internalization. This is very different from CB1 receptors, which are predominantly activated by Anandamide and THC.

CB1 receptors and most known receptors internalize after some degree of use for repair or to regulate the number of available receptors. Cannabinoid receptor internalization as a result of fatigue from heavy marijuana use is the main culprit in marijuana tolerance, for instance.

The functional selectivity of CB2 makes it tricky to study. Many of the synthetic agonists (activators like THC) of the CB2 receptor also interact to some degree with CB1 and vice versa. As a result, it can be tough to isolate just the effect of activating CB2 receptors when you’re observing in the lab or clinic.

For example, a 2010 study showed a commercially available chemical widely used in CB2 receptor research actually activated a whole lot of different nerve receptors in addition to CB2. This rendered virtually useless the results of previous studies using that chemical to activate CB2 and make assertions about it.

CB2 receptor localization

CB2 receptors also seem to proliferate around sites of trauma — for instance, if you get your arm sliced open, the CB2 receptors immediately start healing back on those damaged nerve cells in much higher concentrations than before. Theoretically, this may mean that CB2 agonists (a generic term for any chemicals that activate a receptor) play some role in healing and pain-killing of injuries. The real medical implications of CB2 localization remain murky.