Mechanism of Action

The Cannabinoid Receptor System

Only in the last two decades, a natural cannabinoid receptor system has been discovered in the human body. It is by interacting with these receptors that cannabinoids exert many of their pharmacological effects. The discovery of the cannabinoid receptor system has sparked renewed interest in the therapeutic potential of cannabinoids by providing important new targets for drugs. There are at least two types of cannabinoid receptors in mammalian tissues, CB1 and CB2. CB1 receptors are present in the brain and spinal cord and in certain peripheral tissues. CB2 receptors are expressed primarily in immune tissues. There is preliminary evidence to suggest that additional cannabinoid receptor types may exist.

 

Receptor Distribution

CB1 receptors are widely distributed but are particularly abundant in some areas of the brain including those concerned with movement and postural control, pain and sensory perception, memory, cognition, emotion, autonomic and endocrine functions. They are also found in appetite regulating areas such as the hypothalamus as well as reward centres such as the lymbic system and have therefore been implicated in food intake. More recently, CB1 has been isolated in tissues that are important for energy metabolism such as the liver, adipose (fat) tissue and skeletal muscle. The second type of receptor, the CB2 receptor, can mediate regulation of cytokine release from immune cells and of immune cell migration in a manner that seems to reduce inflammation and certain kinds of pain.

 

So although the endocannabinoid system interacts with many neurotransmitter/neuromodulator systems it is important to note that phytocannabinoids have the ability to interact with all sorts of cellular pathways implicated in a range of diseases such as cancer and metabolic syndrome.

 

Receptor Modulation

Cannabinoids act as ligands (a small molecule able to dock onto the binding site of a protein) conferring their ability to modulate a receptor’s behaviour and consequently their downstream biological pathways. Although the phytocannabinoids all have similar structures, they display a remarkably wide array of actions at each of the different receptors that are now thought to contribute to the endocannabinoid system (such as cannabinoid receptors, transient receptor potential [TRP] channels, melatonin and serotonin receptors, the PPARs and a host of orphan G-coupled receptors). For example it is known that THC positively regulates the CB1 receptor whereas it is negatively regulated by THCV; interestingly CBD has very little action at this site whatsoever.

 

It is important to note that terms positive and negative regulation can be broken down further into a range of subtle but important physiological actions.

 

Over the last few decades, when the pharmaceutical industry discover a receptor responsible for a particular disorder, they screen batteries of small molecules and compounds to identify any that could be used to treat that disorder. Often they have concentrated on those that exert the greatest effects, often referred to as full agonists or inverse agonists, in the hope that very small doses could lead to improved symptoms within patients in the clinic. Clearly there are circumstances where highly active compounds leading to absolute maximum or minimum receptor regulation may not offer the optimum pharmaceutical profile. In some families of receptors, especially those that have a constitutive activity, a partial agonist would offer a better solution. Endocannabinoids act as partial agonists, playing modulatory roles, and because phytocannabinoids behave in a similar fashion they can offer help within a dysregulated endocannabinoid system. GW are particularly well placed to explore these therapeutic advantages.


Positive Regulation:

This animation differentiates full agonists (usually synthetic compounds) and partial agonists (especially useful in systems such as the ECS which are under tonic control):

Negative Regulation:

This animation illustrates the difference between inverse agonism and neutral antagonism at a constitutively active receptor:

Regulation of Neurotransmission

As explained above, neurotransmitter modulation covers just one aspect of the mechanisms that govern cannabinoids therapeutic abilities. However as it was the focus of much early research within the field it is by far the most fully understood mechanism of action.

regulation of neurotransmission

[1]Information is transmitted around the body in the form of electrical impulses that travel through nerves. As the signal reaches the end of the nerve, or axon, the resulting depolarisation stimulates the release of stored vesicles of neurotransmitters (the yellow molecules). These traverse the synapse (the gap dividing two nerves) where they bind to receptors on the post-synaptic cell.  Activation of these post-synaptic receptors then initiates a series of events.

[2]One of these series of events is the release of Endocannabinoids (the red molecules) which are synthesised and released locally and function as a retrograde transmitter.

[3]The endocannabinoids travel in the opposite direction to the initial neurotransmitters, backwards across the synaptic cleft, and bind to pre-synaptic CB1 receptors (the light blue receptors). This feedback allows pre-synaptic regulation of transmitter release whereby the binding of endocannabinoids will retrogradely inhibit the release of further neurotransmitters, whether the neurotransmitters are inhibitory (e.g. GABA) or excitatory (e.g. glutamate)

[4]Phytocannabinoids are able to mimic the action of these endocannabinoids. In this way, they are able to augment the effect that endocannabinoids have in regulating the transmission of impulses from one nerve to another.

 

 

References:

Russo EB, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Medical Hypotheses. 2006;66(2):234-46.

Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT-1a receptors. Neurochemical Research. 2005;30(8):1037-43.

McPartland JM, Guy G. 2004. The evolution of Cannabis and coevolution with the cannabinoid receptor – a hypothesis. In: Guy, G.; Robson, R.; Strong, K.; Whittle, B. ed. The Medicinal Use of Cannabis, pp. 71-102. London: Royal Society of Pharmacists.

McPartland JM, Russo EB. Cannabis and cannabis extracts: Greater than the sum of their parts? Journal of Cannabis Therapeutics. 2001;1(3-4):103-32.