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Introduction
01
The endocannabinoid system: a highly complex component of the human organism
The endocannabinoid system (eCB system) is an endogenous neurohumoral regulatory system: in addition to its function in the central nervous system (CNS), it is also involved in the control of the immune system and other systems of the human organism.1
The brain and many other organs naturally contain cannabinoid (CB) receptors and endogenous messengers – endocannabinoids – that interact with them. The main function of the eCB system is homeostatic regulation, i.e. it ensures a balance in the organism by maintaining the normal functioning of the body – especially the nervous system and the immune system.2-4 In addition, it is involved in the modulation of pain sensation.5
The endocannabinoid system
(eCB system) consists of
Cannabinoid
receptors
Endocannabinoids
Enzymes for the synthesis and degradation of endocannabinoids
The human endocannabinoid system
02
Cannabinoid receptors in the body: starting point for the effect of medical cannabis
So far, research has mainly focused on two cannabinoid (CB) receptor types:
Type 1 cannabinoid receptors (CB1)
Type 2 cannabinoid receptors (CB2)
Both primary receptors (CB1 / CB2) are expressed in many tissues and organs of the body and affect the signaling pathways within the cells. Thus, they are integrated into the body’s own pain sensation system and also modulate important functions in the cardiovascular and gastrointestinal system as well as in the immune system.7,8
Type 1 cannabinoid receptors (CB1) occur predominantly on nerve cells (neurons), type 2 cannabinoid receptors (CB2) mainly on cells of the immune system (mast cells, B and T lymphocytes) (see figure).9
CB1 receptors are most commonly found in the central nervous system (CNS), i.e. in the brain in the basal ganglia, hippocampus and thalamus. These areas of the brain play an important role in regulating stress and anxiety. Overall, the CB1 receptors influence numerous neurotransmitters and neuromodulators.9
CB2 receptors are mainly located in the periphery, where a particularly large number can be detected on cells and tissues of the immune system.3,10,11
In addition to the two primary CB1 and CB2 receptors, a whole series of additional receptors has now been detected. These include, for example, GPR55, GPR119, GPR18, PPAR and the vanilloid receptors (TRPV).12-14
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CB1
CB1 receptors are predominantly located in the central nervous system
CB2
CB2 receptors are mainly found in the immune system
Localization of primary cannabinoid receptors in the body.
Endocannabinoids
03
Endocannabinoids: endogenous messenger substances for a variety of bodily functions
Endocannabinoids can dock like a key to G protein-coupled receptors (lock) of cells.
Endocannabinoids (eCBs) act as natural, inhibitory messengers by attaching to cannabinoid receptors of the cells (endogenous ligands).
They can dock - like a key - to G-protein-coupled receptors (lock) of cells (see figure). In this way, they convey information to the brain, the immune system and other organs and thus initiate cell reactions. The best researched endocannabinoids to date are anandamide (AEA) and 2-Arachidonylglycerol (2-AG).6
Enzymes for the synthesis and degradation of endocannabinoids
Both anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are synthesized in the body as needed. The degradation of the two eCBs is carried out by enzymes, i.e. by monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH). eCB levels and the effect of eCBs on the receptors influence the activity of the degrading enzymes.6
Blockade of neuronal release of neurotransmitters as well as neuromodulators by binding the eCBs to CB1 receptors.
Mechanism of action of the endocannabinoid system
04
Mechanism of action of the endocannabinoid system
In contrast to most neurotransmitter systems, the transmission of signals in the eCB system occurs retrogradely, i.e. there is a retrograde regulation of the neuronal release of neurotransmitters (GABA, glutamate) as well as various neuromodulators (e.g. dopamine, serotonin, acetylcholine).3
The transmission of excitation from one cell to another occurs in the synapse. As a rule, a signal in chemical form is transmitted from the presynaptic neuron to the postsynaptic neuron (see Figure (1)).
Endocannabinoids (eCBs) are synthesized in the postsynaptic neuron, released into the synaptic left (2) and bind retrogradely to the CB1 receptor of the presynaptic neuron (3). Binding of eCBs to the CB1 receptor on the presynaptic neuron temporarily or persistently blocks transmitter release at the affected synapse(4). This mechanism of action allows modulation of neuronal signalling pathways according to homeostatic requirements.6
The signal transmission of the CB2 receptors is currently less well known: it is involved in the release of cytokines, according to which an anti-inflammatory effect could be assumed.15
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The endocannabinoid receptors
In the central and peripheral nervous system, there are many interactions between the CB1 and CB2 receptor systems, neurotransmitters and neuromodulators.16 Only the CB1 receptors are associated with psychotropic effects, while the CB2 receptors lead to immunomodulatory effects.6 There is also evidence that GPR receptors link the immune system with the nervous system and the endocrine system.1
Interaction of endogenous systems with the endocannabinoid system
The network of the endocannabinoid system with numerous other endogenous systems can have diverse effects on the following functions:
Emotional
Psychological
Cognitive
Mental
Physical
Motor
Sensory
Organic
An additional administration of cannabinoids can – depending on the individual clinical picture of the patients – support the function of the endocannabinoid system.
References
Status: 2021
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Hoch E, Friemel CM, Schneider M. Cannabis: Potenzial und Risiko. Cannabis, Cannabinoide und das Endocannabinoidsystem 2019. https://link.springer.com/chapter/10.1007%2F978-3-662-57291-7_1 (last visited on 30 June 2021).
Lutz B et al. The endocannabinoid system in guarding against fear, anxiety and stress. Nat. Rev. Neurosci. 2015; 16:705–18.
Turcotte C et al. The CB2 receptor and its role as a regulator of inflammation. Cellular and MolecularLife Sciences 2016; 73:4449-70.
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Grotenhermen F, Häußermann K. Cannabis – Verordnungshilfe für Ärzte. (Wissenschaftliche Verlagsgesellschaft Stuttgart, 2017).
Grotenhermen F, Müller-Vahl K. Das therapeutische Potenzial von Cannabis und Cannabinoiden. 2012. www.aerzteblatt.de.
https://www.aerzteblatt.de/archiv/127598/Das-therapeutische-Potenzial-von-Cannabis-und-Cannabinoiden (last visited on 30 June 2021).Maldonado R, Baños JE, Cabañero D. The endocannabinoid system and neuropathic pain. Pain 2016; 157: 23–32.
Häuser W. et al. European Pain Federation (EFIC) position paper on appropriate use of cannabis-based medicines and medical cannabis for chronic pain management. Eur. J. Pain (United Kingdom) 2018; 22:1547–64.
Brown A. Novel cannabinoid receptors. Br J Pharmacol 2007; 152 (5):567-75.
Lu HC, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiat 2016; 79(7):516-25.
Zygmunt PM et al. Vanilloid receptors on sensorry nerves mediate the vasodilator action of anadamide. Nature 1999;400(6743):452-57.
Cristino L, Bisogno T, Di Marzo,V. Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat. Rev. Neurol 2010;16: 9–29.
Grotenhermen F: Cannabinoids. Curr Drug Targets CNS Neurol Disord 2005;4:507-30.