French doctor explains us endo-cannabinoid system

The Endocannabinoid System ( ECS ) has been  uncovered  about twenty years ago after the discovery of Δ9 tetrahydrocannabinol (THC) , its synthesis and specific mode of action (psychoactivity) ( Mechoulam 1964) ,the discovery of the cannabinoid receptors CB1 (Howlett 1986) and CB2 (Munro 1993) and the identification of the 2 ligands Anandamide (AEA Devane 1992) and 2-arachydonyl glycerol (2-AG Mechoulam 1995). It is a wide web of intercellular communication, essential for the maintenance of a stable internal milieu : HOMEOSTASIS; Biological Harmony even though there may be fluctuactions in the external environment by pollution, life style, poor diet or genetic variations or epigenetics. This neuromodulatory ubiquitous system, broadly expressed by the existence of cannabinoid receptors on every tissue and every cell of all biological systems ,commands the physiological balance for the control of body temperature , sleep,  food intake appetite nausea  body weight, pain, memory, learning, mood, emotional regulation, motivation, reward and addiction, fertility, reproduction, pre and post natal development, motricity.

In case of cell homeostasis disruption, the ECS is activated on a space and time selective, key and lock ligand-receptor specific manner. The ECS exists in all vertebrates, humans from a very early stage of embryogenesis The ECS includes: The 2 endocannabinoid ligands 1)AEA and 2)2-AG, lipid compounds, are retrograde messengers, synthesized

• A)on demand B)when C)where they are needed and quickly degraded; they act on the presynaptic neuron to modulate neurotransmitters release whereas neurotransmitters and hormones are stored
• AEA is a partial agonist on CB1R and CB2R , affects memory and extinction of fear memories ( post traumatic stress disorder  PTSD ), emotions, reward, addiction, analgesia, embryo implantation, inhibition of cell proliferation, induction of apoptosis
• 2-AG the most abundant, is a full agonist for CB1R and CB2R, regulates food intake, energy metabolism, mood, sexual behaviour, anxiety depression, addiction, inflammatory, neuro-inflammatory processes, immune responses, proinflammatory mediators after injury, pain control, certain types of cancer cells proliferation

The receptors ,located in cell’s membrane inform the cells ; a receptor is a protein which interacts with substances outside of the cell to produce an answer in the cell 

• CB1R for regulation of body temperature, fluid balance, sweating, appetite, ion concentration, sugar levels, located ++++in basal ganglia (motor activity), hippocampus (memory) susbstantia nigra ( movement ), rhombencephale ( analgesia ) cerebellum, ( gait balance) olfactory bulb (smell) + cerebral cortex, septum, amygdala ( emotions), hypothalamus, neurons astrocytes  oligodendrocytes; this high density leads to a major cerebral and psychoactive expression in peripheral organs eyes, heart, respiratory, digestive, reproductory systems , kidneys , muscles , skin
• CB2R for regulation of immune responses, inflammation, cell migration, apoptosis, bone density, new tissu production, pain controllocated +++ in microglia, neurons astrocytes, tonsils, thymus, spleen, cells of the immune system ( macrophages, lymphocytes B and T, monocytes, mast cells), skin
• Other receptors involved : GABA TRPV1, GPR 55, PPAR
• On all these receptors ligands AEA,2-AG, and phytocannabinoids THC and cannabidiol ( CBD ) CBG, CBN, CBC, THCV  can either be agonists partial agonists, full agonists, inverse agonists…allosteric modulators positive and negative  thus varying the receptors’s expressions

The enzymes responsible of the synthesis and degradation of the endocannabinoids : Fatty Acid Amide Hydrolase (FAAH ) for AEA and MonoAcylGlycerolLipase ( MAGL) for 2-AG. The clinical ECS deficiency syndrome (Russo) by insufficiency of production of endocannabinoids or cannabinoid receptors  could be  the cause of many pathologies :

• hypersensitivity to pain
• headache
• migraine
• irritable bowel syndrome ( IBS)
• fibromyalgia
• depression

Supplementation with phytocannabinoids might improve this deficiency and alleviate symptoms Phytocannabinoids interact within the ECS :THC activates CB1R and produces psychoactivity; CBD interacts on many receptors ( 5-HT , GPR55 , TRPV1 … ) on the cerebral level upon memory anxiety, epilepsy, nausea spasticity, increases AEA level, extends and reduces THC’s psychoactivity …. The ECS  can be stimulated :

• after exercises: aerobic, intensive sport ( runners’s  high euphoria) breathing exercises, yoga, meditation , acupuncture, all pleasure and well-being physical activities
• an omega-3 rich diet, black chocolate, turmeric, tea  herbal teas (Echinacea)  black pepper ( β caryophyllene terpene ), magnesium

ECS receptors can be damaged by pesticides, phtalates, alcohol The ECS is predominant over the different biological including  immune and cerebral systems to protect the organism; Comprehension of ECS will allow prevention, care of multiple diseases, the treatments of which carry actually many side effects, few relapses and rare cures Manipulations of the ECS (ex by inhibiting the degrading enzymes) will offer huge therapeutic opportunities for nearly all diseases human beings of all ages suffer : pain, anxiety, depression, stress , neurodegenerative pathologies, epilepsy, cancer …., Glossary

• neuromodulation= regulation of synaptic activity , of nervous transmission between neurons throughout the brain to protect neurons
• retrograde= released in the post-synaptic area this substance acts on the pre-synaptic site
• key-lock system = a specific key which will fit in a precise lock
• agonist = a compound that activates a receptor , a full agonist is more powerful than a partial agonist , an inverse agonist induces a response opposite the agonist effect , antagonists on binding on the receptor orthosteric site block the drug & ligand agonist response
• allosteric modulators = on binding on a receptor’s allosteric sites a compound enhances ( positive) or reduces ( negative) the ligand’s response when binding on an orthosteric site of the same receptor
• apoptosis = programmed cell death ; cells trigger own self destruction
• nociception= perception of pain

Article written by Dr. Janine GASTON-NHAN Article formatted and published by Alpha-Cat