As we  established in our previous section, there are three different varieties of cannabinoids:  Phytocannabinoids, including THC, CBD and other plant cannabinoids;  Synthetic  or laboratory produced cannabinoids such as Dronabinol or Marinol;   and internally produced substances known as Endocannabinoids.  These are long chain polyunsaturated fatty acids produced  (by oxidation of 20-carbon fatty acids) from arachidonic acid and other membrane phospholipids. 


Endocannabinoids  act  as  inter-cellular  signaling-molecules.  But these neurotransmitters are not stored within the body.  Rather, they are produced  in an "on demand" manner.   They then act through retrograde signaling, meaning that they are released from within one cell and then activate cannabinoid receptors on other, nearby cells.  


Typically, just a small group of ligads act upon the endocannabinoid system.  So far, only six have been identified. (See Side Bar: Endocannabinoids)  Of these, only two (Anandamide and 2-AG) are considered predominant.  THC and other phytocannabinoids are able to mimic these endogenous signaling molecules due to the similarities in their structures. (See illustration below.)  The similarities in the configuration of endocannabinoids and phytocannabinoids permits THC and other cannabinoids to access a vast complex of chemically activated cellular switches  normally reserved for endocannabinoids.   This interaction is responsible for most of the pharmacological effects of both endocannabinoids and plant phytocannabinoids.









Cannabinoid receptors, are members of the guanine-nucleotide-binding protein (G-protein) coupled receptor family, hence their name:  G-protein Coupled Receptors or GPCRs.   GPCRs,  are widely distributed in cells in the brain, central nervous system and immune system.  


GPCRs pass through the inner and outer cell membrane a total of seven times.  They are organized to include three extracellular and three intracellular loops that have a spiraling,  almost serpentine configuration.  (See illustration: CB1 & CB2 Receptor and Terminal Configuration below). Think of the loops of the Loch Ness monster both rising above and extending below the surface of the water( or in this case, the cell membrane), then imagine these loops also coiling like the wire to an old telephone receiver, and you'll get the idea.  At either end of these loopy receptors are the  terminals to which chemical messengers bind. The inner terminals differ from the outer terminals.  The intracellular portion ends in a C-terminal tail.  The extracellular portion of the receptor, to which cannabinoids bind, ends in an N-terminal tail.  












                                                                                         CB1 and CB2 Receptor and Terminal Configuration



When activated GPCRs inhibit adenylate cyclase activity (in a dose-dependent, stereoselective and pertussis toxin-sensitive manner). Before an available cannabinoid has even bound to a receptor site, the receptor has already reacted to its  proximity by altering the shape of its terminals to better attract the molecule.  The three-dimensional conformation of receptors  determine the cell's functional state so  other changes also take place.  G proteins are activated which facilitate the cell's interaction with cannabinoid molecules.   Once THC or other cannabinoids have bound to  a receptor site, a further cascade of biological reactions ensue.  Other ligands are immediately blocked out and therefore can not exert their usual bio-regulatory functions.  Signal transduction pathways open within and between cells to allow for intercellular response, and phyto cannabinoids  usurp control over cellular bio-regulatory functions such as metabolism, shape, gene expression, and  a number of bodily processes , ranging from sensory signaling to regulating electrolyte balances.  It is the dynamics of these connections and reactions that  produce the therapeutic and psychoactive effects characteristic of cannabis consumption.   (See sidebar: Ways GCPrs Influence the Body.)


The type and location of  receptor sites governs the actions and influences of cannabinoids in the body  There are two predominant CB receptors to which the action of cannabinoids have been attributed.  The two are distributed in different locations in the body, only share 48% amino acid sequence, and also have different signaling mechanisms.  They also differ in their sensitivity to agonists and antagonists.

 

CB1 Receptors


CB1 receptors, also known as CNR1, CNR,  CB-R, CB1A and a number of other abbreviations, are the most  widely distributed type of  G protein coupled receptors.   There are 10 times more  CB1 receptors in the body than the (μ-opioid) receptors responsible for the effects of morphine/opiates.  Normally CB1 receptors regulate the release and synthesis of the body's chief inhibitory neurotransmitter γ-Aminobutyric acid or "GABA", as well as Glutamate and other important neurotransmitters, all of which play  major roles in neural activation and cellular metabolism.  


CB1 receptors are primarily located in the brain. They are especially abundant in the cerebellum, basal ganglia, hippocampus and other parts of the limbic system as well as the spinal cord and nerve cells    Their dense distribution here gives cannabinoids influence over many brain functions such as memory processing, pain regulation and motor control.  The sense of euphoria experienced by cannabis users is a result of  the influence of plant cannabinoids upon CG1 receptors.    They also contribute to the mellow, soothing,  and relaxing effects of cannabis as well as its anti-convulsive properties. 





















Cerebellum









Though the above graphic alludes to the Basal Ganglia's involvement in coordination of movement and control of voluntary motor movements, it fails to mention that they play a role in procedural learning, routine behaviors or "habits" such as grinding teeth or jaw clenching,  eye movements, cognition, and emotions. 

The limbic system includes the olfactory bulbs, hippocampus, amygdala, and several other brain structures and exerts influence over both the endocrine and the autonomic nervous system.  Its functions  include adrenaline flow, emotion, behavior, motivation, long-term memory, and sense of smell.    It is also interconnected with the brain's pleasure center and plays a role in sexual arousal.

The hypocampus, a part of the limbic system,  influences learning and certain types of memory (short term), spatial navigation, and verbalization. It is the most electrically excitable portion of the brain and is often the focus of epileptic seizures.   Damage to the hypocampus often leads to hyperactivity and behavioral issues.  Deterioration of the hypocampus is often found in Alzheimers disease. 


The concentration of cannabinoids is low in the brain stem, however.   This explains why cannabis use is not associated with sudden over-dose death due to depressed respiration, for example.  CB1  receptors may also found in lower numbers in some peripheral organs and tissues including the liver, spleen, white blood cells, endocrine glands and parts of the reproductive and urinary tracts.

There are no CB1 receptors in the medulla oblongata.   This is the part of the brain stem responsible for respiratory and cardiovascular functions.  Their absence makes fatal overdose on cannabis a biological impossibility. 




CB2 Receptors

THC and some other cannabinoids are ligands for another set of GPCRs known as CB2 receptors.  The two are similar in respect to their agonist recognition, but the primary endogenous ligand for CB1 receptors is anadamide while the principal  ligand for the CB2 receptor is 2-arachidonoylglycerol (2-AG).   Both CB1  and CB2  mediate their action through the inhibition of adenylyl cyclase via a pertussis toxin-sensitive GTP-binding regulatory protein.  But CB1 is also associated with inhibition of N-type calcium channels in neuroblastoma-glioma cells  and Q-type calcium channels in AtT-20 cells while CB2 receptors do not seem to display similar activity.  In addition, CB2 receptors feature some structural differences from CB1 receptors.  For instance they are smaller.  CB2 receptors are made up of approximately 360 amino acids whereas  the CB1 receptor is 473-amino-acids-long.   Their areas of distribution differ as well.   CB2 are most abundantly concentrated on the cells of the  immune system including B-cells,  natural killer cells,  monocytes, polymorphonuclear neutrophil cells, T8 cells, and T4 cells. They can also be found within the tonsils, and in greater density in the spleen.   (Immune cells also express CB1 receptors, although far less densely than CB2, just as there are some CB2 receptors in the brain and nervous system in spite of  their predominance within the immune system.)


Considering that the vast majority of CB2 receptors are distributed it should come as no surprise that CB2 receptors account for the anti-inflammatory and other therapeutic effects of cannabis.  When cannabinoids  inter-react with CB2 receptors they act as immunomodulators.  This means they increase some immune responses while decreasing others.  One important function of CB2 receptors is the regulation of cytokine release.  Cytokines , which include interleukins and lymphokines, are cell signal molecules  that  control  interactions and communication between cells and influence their behavior.  They also modulate immune cell migration .  Among the cytokines  are tumor necrosis factor and the interferons.  These trigger inflammation and respond to infections.



Additional Cannabinoid Receptors

Though the scope of their actions have yet to be described, growing evidence of additional cannabinoid receptors, that are neither CB1 nor-CB2, exists.  

The orphan receptor GPR55,  which is expressed in the caudate nucleus and putamen, structures that make up the basal ganglia, could be re-categorized as a cannbinoid receptor and designated CB3.  Though GPR55 does not activate either CB1 or CB2 receptors, it displays a smiliar amino acid sequence in the binding region and responds to a variety of both endogenous and exogenous cannabinoid ligands including  CBC, where it was found to  be an antagonist.  It became the focus of extensive research when it was mistakenly thought responsible for the ability of cannabinoids to lower blood pressure.

The N-arachidonoyl glycine (NAGly) receptor GPR18 is another suspected cannabinoid receptor.  This "orphan" receptor has been found to  respond to compounds such as abnormal cannabidiol to produce  cannabinoid-like effects on blood pressure and inflammation without activating CB1 or CB2 receptors.

Yet another receptor, GPR119, has been suggested a fifth possible candidate as a cannabinoid receptor.  GPR119 is expressed predominantly in the pancreas and gastrointestinal tract and activation of the receptor is thought to cause a reduction in food intake and body weight gain.  It has also been shown to regulate incretin and insulin hormone secretion.  Research is being directed toward the future possibility of  new drugs that would act on this receptor as novel treatments for obesity and diabetes.

Clearly, there is still much we do not know and further study is needed before we fully understand how the cannabinoid system functions and the full scope of therapeutic benefits cannabis might have on the human body.   For further information on how cannabis works, please continue to our section on
Terpenes.


Endocannabinoids


Anandamide, Arachidonoylethanolamine or AEAC22H37NO2
An essential fatty acid, neurotransmitter, and the body's main endocannabinoid.  Anandamide affects CB receptors in the central and peripheral nervous system  and is a full agonist of both CB1 and CB2 receptors.  It plays a role in pain, depression, appetite, memory, fertility and sensations of pleasure.   "Anadamide" is Sanskrit for bliss. 

2-Arachidonoylglycerol or 2-AG 

C₂₃H₃₈O₄  
Another primary, and the most abundant, endocannabinoid,  2-AG effects  CB receptors in the central and peripheral nervous system.  Though it is a full agonist of both CB receptors, and it is the primary ligand  for the CB₂ receptor.  2-AG  plays a complex and important role in various bodily processes including immune system functions, pain management, and inflammation as well as appetite regulation and inhibition of cancer cell proliferation.

2-Arachidonyl glyceryl ether  or Noladin ether - C23H40O3
Binds primarily  to the CB1 receptor and only weakly to the CB2 receptor.   It shows agonistic behaviour on both receptors and is a partial agonist for the TRPV1 channel.  Studies have shown it to be neuroprotective.  It also lowers Intra-ocular eye pressure.

 N-Arachidonoyl dopamine (NADA) 

C28H41NO3
An agonist of the CB1 receptor and the transient receptor potential V1 (TRPV1) ion channel, a member of the vanilloid receptor family.


Virodhamine (OAE)

C22H37NO2
A full agonist at CB2 and a partial antagonist at CB1, but it behaves as a CB1 antagonist.  Its molecular structure is the opposite of the amide linkage found in Anadamide.  Due to this opposite orientation, the molecule was named "Virodhamine" from the Sanskrit word VIrodha, which means opposition. Concentrations of virodhamine in the human hippocampus are similar to those of anandamide, but they are 2- to 9-fold higher in peripheral tissues that express CB2.  Studies have shown that Virodhamine lowers body temperature



Lysophosphatidylinositol (LPI) 

C25H49O12P

Ways  GPRs Influence the Body


VISION
GPCR reactions help translate electromagnetic light radiation into cellular signals.



TASTE
GPCRs in taste cells mediate response to bitter- and sweet-tasting substances.


SMELL
The olfactory epithelium that binds odorants (olfactory receptors) and pheromones (vomeronasal receptors) are G-protein receptors.

BEHAVIORAL & MOOD REGULATION
GPCRS interreact with several different neurotransmitters, including serotonin, dopamine, GABA, and glutamate.

MEMORY

GPCRs are widely distributed within the Limbic System, which is involved in long term memory; and the Hypocampus of the Limbic System, which influences short term memory.



MOTOR CONTROL
GPCRs are found in the basal ganglia of the fore-brain which is associated with control of voluntary motor movements and the Hypocampus which is involved in spatial navigation.


APPETITE
A response to stimulation of GPCRs found within the olfactory bulbs in the brain.

DIGESTION

Signaling molecules (Δ9-THC among them) act on GPCRs to modulate gastrointestinal activity,


IMMUNITY
GPCRs regulate immune system activity and inflammatory response.

HEART RATE * BLOOD PRESSURE *  DIGESTION
Modulation of Autonomic nervous system transmissions controlling blood pressure, and heart rate;  activates protein (MAP) kinases.

CELL DENSITY SENSING

GPCRs regulate GABA which plays a major role in cellular function and metabolism.


BONE

CB2 signaling helps regulate bone mass


HOMEOSTASIS MODULATION
GPCRs control water/electrolyte balance.

TUMOR GROWTH & METASTASIS


Over half of all known drugs work through G-protein receptors!



Cannabinoid Receptors aka G Protein-coupled Receptors

     Cannabinoid receptors are divided into 2 main subypes:  CB1 and CB2.

CB2 Receptor Distribution


B-cells
Lymphocytes (white blood cell) involved in the creation of antibodies.

Natural Killer Cells
Cytotoxic lymphocytes critical to the immune system. they can react against and destroy other cells without prior sensitization to them and play an important role in eliminating cancer cells.

 Monocytes
White blood cells created in the bone marrow and which have the ability to ingest foreign matter.  They play an important role in the immune system and are instrumental in protecting the body against infection.

Polymorphonuclear Neutrophil Cells
 The most abundant type of white blood cells.  Formed in stem cells and the bone marrow, these granulocytes are first responders to trauma and inflammation.

T8 cells
A type of white blood cell that targets and kills damaged cells, cells infected with a virus and cancerous cells.

T4 cells
Thymus derived lymphocytes which stimulate the activity of natural killer cells, gamma interferon, and suppressor T8 cells.