Our body and the endocannabinoid system

Why and how do cannabinoids actually work? This is due to the body's own endocannabinoid system. You can read more about this here in our article.

The endocannabinoid system (abbreviation for endogenous cannabinoid system) includes the cannabinoid receptors CB1 and CB2 with their natural ligands and downstream intracellular signal processing and effector mechanisms.

The history of the endocannabinoid system

The active ingredients of the cannabis plant, the cannabinoids, gave rise to the name and led to the discovery of this system. The discovery of these specific receptors inevitably led to the realization that there must also be endogenous ligands (endocannabinoids)66 for these receptors.

In 1992, Devane et al, were able to isolate and subsequently synthesize from pig brains the first substance that binds to the CB1 receptor: a condensation product of arachidonic acid and ethanolamine, N-arachidonylethanolamide (AEA), often referred to as anandamide (in reference to the Sanskrit word for "bliss": ananda). In 1993, γ-linolenoylethanolamide and docosatetraenoylethanolamide followed as further substances, in 1997 2-arachidonyglycerol (2-AG), in 2001 2-arachidonylglyceryl ether (noladine ether) and in 2002 the O-arachidonylethanolamide (virodhamine) .

N-palmitoylethanolamine (PEA) is another substance with endocannabinoid-like activity that occurs in the stratum granulosum of the skin and has, among other things, an antioxidant protective effect against UVB radiation.

2-Arachidonyl glycerol and arachidonylethanolamide are derivatives of arachidonic acid and are formed via enzymes in lipid metabolism.

Cannabinoid receptors

Cannabinoids activate so-called cannabinoid receptors. Two cannabinoid receptors have been described so far, both belonging to the class of G-protein coupled receptors. Both cannabinoid receptors modulate different ion channels. Furthermore, various signaling pathways within the cell are influenced by cannabinoid receptors:

Cannabinoid receptor 1 (or CB1 for short) is found predominantly in neurons. It is most abundant in the cerebellum, basal ganglia, and hippocampus. However, it is also found in the peripheral nervous system (e.g., in the intestine).

Cannabinoid receptor 2 (or CB2 for short), on the other hand, is found predominantly on cells of the immune system and on cells involved in bone formation (osteoblasts) and breakdown (osteoclasts).

Agonists and antagonists

The cannabinoid system can be influenced pharmacologically. Cannabinoids have an agonistic effect, see dronabinol. The CB1 blocker rimonabant, which has been available in Germany since September 2006 for the treatment of abdominal obesity, has an antagonistic effect and could also gain medical significance as a supportive drug for withdrawal from nicotine or alcohol.

In the field of research, a variety of agonists and antagonists are also being used. This makes it possible to selectively block or activate one of the receptor types without affecting the other.

Functional significance

Little is yet known about the functional significance of the endocannabinoid system. The distribution of the receptors already suggests a number of possible functions. For example, the CB2 receptor is thought to play an important role in the regulation or modulation of the immune system. Since the brain regions where the CB1 receptor is predominantly found play an important role in memory (hippocampus and cerebellum) as well as movement regulation (basal ganglia and cerebellum), it is reasonable to assume that endocannabinoids influence learning and movement processes.

Endogenous cannabinoids are released from postsynaptic neurons into the synaptic cleft and act retrogradely on the presynaptic neuron. Their effect is based on a down-regulation of transmitter release at the affected synapse. This effect is mediated by three different mechanisms:

Decreasing the activity of presynaptic calcium channels,

increase in the activity of postsynaptic calcium channels, and

Inhibition of adenylate cyclase, thereby decreasing the activity of protein kinase A.

In the cerebellum in particular, canabinoid-dependent forms of synaptic plasticity have already been identified. These are called depolarization-induced suppression of excitation (DSE) and depolarization-induced suppression of inhibition (DSI). Both occur at Purkinje cell synapses, DSE at excitatory synapses and DSI at inhibitory synapses.

However, a receptor-independent effect of endocannabinoids has also recently been found at Purkinje cells. Endocannabinoids thus directly inhibit P-type calcium channels in these cells.

Endogenous activation of the CB1 receptor is necessary for the correct adaptation of the eyelid closure reflex. This form of associative learning occurs exclusively in the cerebellum.

Current research indicates that the presence of the CB1 receptor is necessary for the erasure of certain negative memories. Therefore, endocannabinoids are thought to play an important role in certain anxiety disorders.

Other physiological processes in which they may be important include pain states, sleep induction, appetite and motility control, temperature control, and neuroprotection.

Studies with sometimes conflicting results have been conducted in patients with

movement disorders, such as dystonia, Gilles-de-la-Tourette syndrome, Huntington's disease and Parkinson's disease

• multiple sclerosis (to affect ataxia, neurogenic bladder emptying disorder, pain, spasticity, tremor and inhibition of neurodegeneration

• other diseases associated with spasticity (paraplegia, AIDS encephalomyelopathy)

• various neurological pain syndromes (various forms of headaches, neuralgias, neuropathies)

• epilepsy

• traumatic brain injury, neurodegenerative diseases, amyotrophic lateral sclerosis (for neuroprotection)

• postoperative and chemotherapy-induced vomiting