Please make sure to like this article and subscribe to my blog for future articles and notifications in this article, we’re going to discuss the major mechanism of cannabinoids, specifically the mechanism that show How Does CBD Oil Work for pain?
That’s what we’re going to focus on here. So, first of all, let’s define what a cannabinoid is and How Does CBD Oil Work for pain?
So cannabinoids are small molecules. There are neurotransmitters, some of which are synthesized inside the body and dodging asleep. And How Does CBD Oil Work for pain?
How does CBD Oil work for pain? Others are administered or taken exogenously and their molecules that really serve to do two major things: they’re going to regulate neuron function, which is what we’re going to focus on here, and they also play some roles in reducing inflammation. So they are intrinsically anti-inflammatory.
The first class of cannabinoids are those that are made naturally via biosynthetic pathways by your own cells. These are called endocannabinoids and there’s really two major ones. The first one has the abbreviation 2 AG. That’s this molecule right here. This is called 2 arachidonic glycerol, it’s derived from arachidonic acid, there’s another one abbreviated AEA. This is an and amide, also derived from arachidonic acid.
They are made by your own cells. There are also what we can call EXO cannabinoids. These are typically the cannabinoids that you would have in marijuana or some other source, like CBD oil. We’Ll talk about that in a little bit later, but those are going to be cannabidiol, also abbreviated, CBD and then also the infamous tetrahydrocannabinol THC, which is only legal in certain states and to varying degrees.
We’ll come back to these in a little bit, but we’re going to focus on the mechanism of how these cannabinoids are going to reduce the perception of pain. So we’re going to imagine a situation right here where, on the right side here is a presynaptic neuron on the left side, this is a postsynaptic neuron, and so the information is traveling in this case from right to left right and we’re going to assume that information.
That’s being propagated between these two neurons is pain, so when we have a painful stimulus, we’re going to have an action potential, that’s running down this axon of the presynaptic neuron, and we know hopefully at this point that action potentials running down the axon eventually will trigger The opening of voltage-gated, calcium blogs in the terminal button of this axon, so calcium, will be in flexing into the cell from the extracellular fluid out here to the intracellular in here we are not actually going to have potassium efflux, so potassium is going to actually for Now remain inside the cell, but we have calcium influx and when we have calcium influx, that’s going to depolarize the membrane of the cell.
It’s going to depolarize the membrane right here and that’s going to trigger neurotransmitter release into the synaptic cleft and specifically the neurotransmitter. That’S going to be released by most neurons that are going to be propagating. The perception of pain is glutamate, so this glutamate is released by the presynaptic neuron. It’s going to diffuse across the synapse and it’s going to bind to a glutamate receptor.
So this receptor right here is a glutamate receptor, it’s situated in the membrane of the postsynaptic neuron. So when glutamate is exocytosed from the presynaptic neuron into the synaptic cleft, the glutamate is going to diffuse down its concentration gradient towards the postsynaptic neuron, and it’s going to bind to this receptor right here. This is actually a glutamate receptor and when glutamate binds to this receptor, that’s going to trigger an initial depolarization of this neuron, and so then you’ll get an action potential.
That’s in going down this axon right here and that’s going to give you pain. That’S the first thing that happens, because if we have a stimulus that is going to cause us to perceive pain, we need to have the action potential from the presynaptic neuron be transferred to an action potential in the postsynaptic neuron. So that makes sense. But there’s another thing that also happens – and this is the focus of this article – we’re also going to have the release of endocannabinoids.
So, first of all, let’s talk about how they’re released and then why so, ultimately, when glutamate binds to this receptor, it’s going to activate a series of three enzymes, this first one PLC – this is phospholipase C, so phospholipase C is an enzyme that you may have seen In a bio signalling topic in biochemistry it’s going to take this membrane, lipid called pip2 or pip that stands for a phosphatidyl inositol 4-5.
This phosphate normally for obvious reasons. We abbreviated pip to phospholipase c, is going to break that apart into two things, one is IP. 3 and IP 3 is a second messenger. That’Ll go inside the cell and do various things. One of those things is trigger, calcium into the cytosol. But the major thing here is that we also get this molecule called diacylglycerol abbreviated. Dag this dag, that’s generated by the action of phospholipase c, is just going to kind of stay in the membrane.
Okay, because it’s still hydrophobic and it’s going to recruit this protein called dag l, okay and dag L is going to come up here and become activated. Dag L is an enzyme called diacylglycerol lipase right, it’s going to take dag and further lipo lies it into this molecule. To AG right. This is called arachidonic Weil glycerol. This is our first endocannabinoid and once this endocannabinoid is generated by dag L or diacylglycerol lipase, that arachidonic, glycerol or AG will be transported out into the extracellular fluid and we’ll look at the function of that in a couple minutes.
There’s another enzyme here: PL d: this is phospholipase d. This is going to take a unique molecule called nape, which stands for NaCl phosphatidylethanolamine, and it’s going to convert this into a EA also called an and amide, and out of these two Ananda mine is usually the most recognized endocannabinoid. But in any case, whenever PLD forms an and amide from NAIP, this Ananda, my like the 2ag, is going to be transported out into the extracellular fluid, and these two molecules are actually going to bind over here to this receptor.
That’s on the presynaptic neuron called CB. 1, this is a cannabinoid receptor now looking here when two AG and Ananda mine come over here and bind to the cannabinoid receptor, there’s two things that happens: okay, one it stimulates potassium efflux, okay, so this stimulates potassium efflux right here and the other thing that it Does is it actually inhibits the calcium influx? Well, let’s think about what effect each of these things independently would have on the membrane of this presynaptic neuron.
If I stimulate potassium efflux, that would cause hyperpolarization of the membrane, because potassium is moving out and the inside of the cell becomes relatively more positive. So i’m hyperpolarizing the membrane. If you were to inhibit the calcium influx, then calcium canola longer come into the cell. So you’re inhibiting depolarization, so this does two things: one: it inhibits depolarization and two.
It stimulates hyper polarization of the membrane of this presynaptic neuron, and so overall you have hyper polarization now, let’s think about what that hyperpolarization would do well. That hyperpolarization would actually stop the pain signal, or at least would attenuate it to some extent. But why would we want that? Because we had a painful stimuli. We want to perceive pain. It occurs because you don’t want that pain, stimulus to keep going up and up and up or to continue indefinitely.
That would be really bad. Okay. What we want is, we want some pain and we want to dial it back. Okay, so that we don’t feel that pain indefinitely or for it to keep increasing in magnitude. So, in addition to the postsynaptic neuron, initially feeding towards the central nervous system, to give you the perception of pain, we also at the same time release some endocannabinoids which are going to modulate that pain signaling by acting on cb1 receptor or the cannabinoid receptor on the Presynaptic neuron memory and that’s going to decrease the release of glutamate, ultimately by stimulating hyperpolarization and inhibiting depolarization all right, and the major purpose of that is so that the pain signal doesn’t get out of control and keep in mind that, in order to get the release Of glutamate right here, this membrane has to be depolarized, and so that’s why we have the calcium influx from the initial action potential.
But if we inhibit this calcium influx and stimulate potassium efflux, then less and less glutamate is going to be released, and this is a this is more or less stimulus that we can have in a graded fashion. So we can have varying amounts of glutamate release. It’S not necessarily an all-or-nothing phenomenon here: okay, but the point is: is these endocannabinoids are going to feedback on the endocannabinoid receptor or just the cannabinoid receptor and they’re, going to decrease the release of glutamate, which is going to attenuate the pain response? Okay, now that’s extremely important, because we can actually use the cannabinoid receptor, the cb1 receptor as a therapeutic target in order to reduce pain, and actually this is precisely what CBD is used for.
So actually I mentioned that we have to EXO cannabinoids. These are not bio. Synthesized by your body, these are actually made in plants such as the marijuana plant and marijuana in general has two major EXO cannabinoids. One of them is the psychoactive form. This is the one that most people associate with the drug use. This is tetrahydrocannabinol or its full name: Delta, nine tetrahydrocannabinol abbreviated THC, the other one, which is more benign in nature and as actually legal in all 50 states is cannabidiol or CBD.
And so, if you ever see CBD oil, that’s going to be an oil that has a significant amount of CBD in it, but very minimal. In fact, negligible amounts of THC, okay, and so the reason we can use these therapeutically is because cannabidiol and THC, if we’re being really technical, can actually bind weakly to the cb1 receptor, okay, and so what can happen in that case is, for example, CBD, cannabidiol and The bind of the cb1 receptor and that’s going to do the same thing that to a RAC Adoni will glycerol and Ananda my did on the previous slide.
They trigger the activation of the potassium blog, but they inhibit the influx of calcium. I’M going to do the same thing, they’re going to stimulate the flux of potassium, which would tend to cause hyper polarization, and this will inhibit the influx of calcium, which inhibits depolarization and so combined. The net effect is, you have hyper polarization of this membrane which which leads to diminished glutamate release by this presynaptic neuron.
And so, if you have diminished glutamate release, then there’s not as much glutamate or if any binding to this glutamate receptor and so there’s little to no action potentials and so no pain. And so this is kind of the basic mechanism right here as to how cannabidiol is actually going to be able to relieve pain. Put a little bit of a flowchart up here we have CB deactivating CB one. That’s this receptor net hyperpolarization of the presynaptic neuron, which causes less glutamate, release and then decreased pain.
Perception, okay, actually misspelled that right here, but I think you get the idea and a little bit of the differences between cannabidiol and tetrahydrocannabinol are illustrated in this table right here. Thc is the psychoactive ingredient notice, its CBD is non psychoactive. Okay, you’ve probably heard THC gives you the munchies, it’s an appetite stimulant and it tends to promote drowsiness. Thc is actually slightly stronger and its analgesic effect, meaning it’s pain, relief effect, but it does exhibit some side effects such as potentially paranoia and anxiety.
Okay, although usually these are pretty miniscule side effects CBD, on the other hand, has a lot more therapeutic targets. So the fact that it’s neuroprotective it’s anticonvulsant and it behaves as an antioxidant. So it’s able to scavenge for free radicals. Technically THC can do this as well. If you notice you have this aromatic ring right here, so if it ties up a free radical in there, it neutralizes the free radical, and so it can help protect against the effects of inflammation.
It’s anti-inflammatory, it’s also antitumoral. In fact, there have been studies that have shown that CBD well, it’s not completely effective of totally eliminating a tumor cancer. It’s very therapeutic and at least slowing the cancer down and even helping reduce it with combined with other therapies. So CBD is extremely therapeutic and actually what we’re seeing right now is there are trials not yet in humans, but very successful trials and animal models that show several of these things as utilities of CBD.
Now. One thing I wanted to mention before concluding this article is there’s a little bit extra detail here that I didn’t include that’s a little bit irrelevant, but I wanted to make sure to cover it whenever glutamate diffuses across the synapse here and activates, this glutamate receptor, there’s Actually, a couple different kinds of receptors: we can either have an anion, atrophic glutamate, receptor or a metabotropic glutamate receptor in either case we either have calcium influx or a g-protein as being the direct activator of these three enzymes, phospholipase c diacylglycerol, lipase and phospholipase d.
Although the net effect is the same and then when we activate the cannabinoid receptor technically, the the effects on the potassium blog and the calcium blog are due to the levels of cyclic AFP. So really, whenever the cannabinoid receptor is activated, we have an inhibitory g-protein that inhibits the enzyme, adenylate, cyclase or AC adenylate cyclase, recall normally converts ATP into cyclic AM P.
This should actually say ATP, and so, if we inhibit this enzyme, we’re going to drop the levels of cyclic, a and P and so in levels of cyclic, a MP drop. That’s going to be what actually triggers the activation of the potassium blog and the inhibition of this calcium blog. But in any case, I hope this mechanism of pain, transduction right here as it relates to the cb1 receptor, makes sense and hopefully learn how we can actually use CBD as a potential therapy for the treatment of pain.