The above excellent five minute video Visualization of the Endocannabinoid Signaling System by Leanne Chan in 2011 contains great animations and discussion of how cannabinoids act in the body to reduce pain. The visuals are remarkably explanatory but the verbal description assumes specialist knowledge that most people viewing the video lack. In particular an understanding of the complete system by which the body senses and can reduce pain is helpful. A number of clickable references are included for much more in-depth explanations.
So here is a brief layman’s description and interpretation of how the body’s pain systems work and an explanation of some of the other terms and concepts in the video which will hopefully add clarity to what the video says to the average viewer.
The video can be divided into a number of sections. The first section (0:00 – 0:50) explains how pain signals (nociceptive signals) ascend from the spinal cord into the thalamus portion of the brain. This animation in a great article (www.rnceus.com) on the subject shows some details of the process:
The gray area represents a horizontal slice of the spinal cord, which has various columns (or bundles) of nerves which send signals up or down the spinal cord. In this animation pain signals are shown flowing up to the brain. Peripheral reduction of pain is achieved locally, as with the action of aspirin at the site of the pain to reduce sensitivity, or the use of an anesthetic such as Novocain to block transmission of the pain signal at the site, reduction of inflamation via hydrocortisone or stimulation with a TENS unit. Interestingly, the TENS unit by stimulating nerves at the site of pain causes a blockage or reduction in the pain signal at the interneuron (see animation) by causing the release of GABA, resulting in a CNS (central nervous system) effect rather than a peripheral nervous system effect. A very understandable explanation of the body’s pain system is available from the University of Texas Medical School’s Neuroscience Online (see chapters 5-8).
The video discusses the effect of endocannabinoids on what is known as the descending pain modulation system, which is just a means by which the ascending pain signals in the spinal cord can be reduced (modulated), resulting in a reduction of pain. Of course modulation could also act in the reverse fashion to increase pain. This second figure, also from rnceus.com, illustrates the system from where the pain nerve (primary afferent pain neurons) enters the spinal cord to where it reaches the thalamus area of the brain and back to where the descending pathway interacts with the corresponding inhibitory interneuron. The enlarged section shows the interaction of the neurons at this junction. This is the area which the video animates in the second part, starting at 0:50. The enlarged section also lists some of the substances known to have an inhibitory effect on the transmission of pain but fails to include the cannabinoids, probably due to the more recent discovery of cannabinoid receptors.
As the video enters the second section it says “stimulation of the periaqueductal gray is know to produce an analgesic effect. However this neuroregulatory process is thought to be tonically restricted by GABAergic off-cells.” “Tonically restricted” refers to the firing mode of neurons. Phasic firing is the result of a stimulus while tonic firing is a steady state caused, in this case, by “GABAergic off-cells”. The RVM (rostroventromedial medulla), or lower part of the brain which connects to the spinal cord has been shown to have “on-cells” and “off-cells” (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964993) which are related to increasing or decreasing pain transmission. The referenced article at nih.gov gives a nice overview of other descending pain modulation systems, such as those involving the amygdala, norepinephrine and serotonin.
From 00:50 to 1:15 the video begins to discuss the actual mechanism of the analgesic action. In the phrase “Depolarization induced suppression of inhibition” the term “depolarization” refers to how neural synapses work. A synapse is the minute gap between nerve cells (neurons) through which a signal is propagated via an electro-chemical process. Every cell in the body is covered by a membrane which is polarized, which means it has a different potential (voltage) on the inside versus the outside. The typical “resting” potential is about -70 millivolts. This potential is changed by pumping various chemicals such as potassium and sodium through the cell membrane. For example pumping positive sodium ions out from the cell results in a negative charge. An electrolyte imbalance, caused for example by excessive sweating resulting in low sodium, disrupts this signaling scheme with potentially fatal consequences.
There are numerous synaptic feedback mechanisms, re-uptake inhibition mechanisms and the like. Concentrating on the endocannabinoid system only greatly simplifies matters.
From 1:15 to 1:43 the concept of a synaptic feedback mechanism is introduced.
At 1:44 an endogenous (generated within the body) cannabinoid is depicted being synthesized by the cell membrane. The cannabinoids are shown crossing the synaptic cleft and binding with the matching receptors (likely CB1 for CBD products) thereby affecting intracellular signal transduction pathways, reducing the influx of calcium ions into the pre-synaptic neuron causing a decrease in neurotransmitter (GABA) release. This in turn influences the frequency of post-synaptic firing. The result of this is, of course, a reduction in pain.
And that is how the endogenous cannabinoid signaling system is part of the descending pain modulation system works (and this sentence should actually mean something to you now).
At 2:42 the discussion changes to how exogenous cannabinoids can be transferred to the appropriate neurons. Two methods are shown oral, which is slow and subject to detrimental digestive effects and inhaled, which by directly entering the blood is much quicker.
At 3:37 a normal synapse is compared to ones affected by endogenous or exogenous cannabinoids.
At 3:56 the mechanism of action is shown again and the use of cannabinoids for symptoms other than pain, such as anxiety, spasticity, anorexia and nausea. Many other uses of cannabinoids in medicine are currently being investigated. Finding other substances which affect the cannabinoid system is mentioned as a worthy goal and an example of one, a re-uptake inhibitor, is shown. Re-uptake inhibitors of other neurotransmitters such as serotonin are commonly used, as exemplified by Prozac, Celebrex and others.
Hopefully the information in the video as well as the pain system of the human body now makes more sense. If not study of the above reference links and additional references below should be a help.
Descending pain modulation and chronification of pain -https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301419/
By George Bennet,