The Endocannabinoid System:  Master of Body Balance

Overview of the Endocannaboinoid System provided by CFH, Ltd.'s Clinical Science Director, Dr. Karen Hufnagel


What Is It?

  • Master regulatory system - maintains homeostasis and balance in the whole body
  • Extensive system with a web of receptors throughout the body
  • Modulates and influences every single system in the body
  • Functions as a pleiotropic signaling system - a single signal generates multiple responses in numerous tissues containing receptors
  • Not discovered until the late 1980s/early 1990s

Comprised of:

  • Endocannabinoids à signaling molecules
  • Receptors
  • Enzymes that synthesize endocannabinoids
  • Enzymes that degrade endocannabinoids

FAAH (Fatty Acid Amide Hydroxylase)

Monoacylglycerol lipase (MGL)

Endocannabinoids (neurotransmitters):

  • 2 main endocannabinoids; total of 6 have been discovered so far
  • Anandamide [AEA]  

Partial agonist at both the CB1 and CB2 receptors; greater affinity for CB1 receptors

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  • 2-arachidonoylglycerol [2-AG]  

Full agonist at both CB1 and CB2 receptors but with lower affinity than anandamide

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  • Synthesized and released from postsynaptic neurons through a retrograde signaling system - diffuse backward across the synaptic cleft binding to endocannabinoid receptors on the presynaptic side
  • Arachidonic acid derivatives that are synthesized “on demand” based on cellular metabolic needs
  • Modulate the release of neurotransmitters - help keep the body from being too over-stimulated or too relaxed
    • Indirect effects on receptors:
      • Serotonin
      • NMDA
      • Opiate
      • GABA
  • Multiple signal mechanisms - act on cannabinoid receptors other than CB1/CB2 (i.e., TRP receptors)

Receptors:

  • CB1
  • CB2
  • Peroxisome proliferator-activated receptor-γ (PPAR-γ)
  • TRPV1 receptor
  • GPR55, GPR18, GPR119 (G-protein coupled receptors)

G-protein coupled receptors, TRPV1, and PPAR-γ functionally interact with CB1 receptor signaling

CB1 receptors: 

  • Primarily located in the central and peripheral nervous system
  • Important role in cognition, memory, learning, emotion, mood, motor activity, pain and motivation 
  • Exist to a lesser degree in many peripheral organs (such as adrenal gland, adipose tissue, heart, liver, lung, prostate, uterus, ovary, testis, bone marrow, thymus, tonsils)
  • Located pre-synaptically

CB2 receptors: 

  • Primarily in peripheral organs/tissues (including bone, GI tract, etc.) and immune system
  • Modulate cytokine release (impacts pain, inflammation, immune function)
  • Recently, CB2 receptors have been discovered in the brain as well – including pain pathways
  • Located pre-synaptically

Endocannabinoid System Functions

  • Hippocampal neurogenesis
    • Memory
  • Appetite regulation
  • Homeostasis of energy balance and metabolism
  • Regulation of the HPA axis
    • Stress response
    • Emotion regulation
  • Modulation of the immune system
    • Including gut immunity
  • Female reproduction – anandamide regulates timing of embryonic implantation and uterine receptivity…if levels are either too high or too low, risk of miscarriage increases.
  • Autonomic nervous system regulation
    • Including gut motility, heart rate, breathing, etc.
  • Analgesia (pain relief)
  • Inflammation
  • Thermoregulation
  • Sleep
  • Cardiovascular function
  • Physical exercise effects – aerobic exercise (70-80% MHR) increases plasma anandamide levels à responsible for the “Runner’s high”
  • On-demand regulation of other neurotransmitter systems