BACKGROUND
If you have ever taken a painkiller and wondered, how does it know where to dull the pain then this article is for you. There are many over-the-counter pain medications such as Aspirin, Ibuprofen and Naproxen, and these all produce their pain relieving effects in the same way. To discuss how painkillers work though it is important to appreciate how the body works on a molecular level, a topic known as molecular biology. A discussion of molecular biology often results in introducing some aspects of biochemistry, the study of chemical reactions that occur in the body, so some basic elements of both of these topics will be discussed.
TYPES OF PAINKILLER
There are three classes of painkiller, (i) Opiates, (ii) Opioids and (iii) Non-Steroidal Anti-Inflammatory Drugs. Opiates refer to a group of compounds which naturally occur in the poppy plant, they include Morphine, Codeine, and Thebaine. Opioids are man-made compounds that resemble Opiates. They are also effective at treating pain, and include compounds like Fentanyl, Oxycodone, and Methadone. The supply and sale of opiates and opioids is restricted since they are addictive. The final class of painkiller, NSAIDs, are available to buy over the counter.
Opiates and Opioids generate their painkilling effects in similar ways which will not be discussed here. Only the painkilling effects of NASIDs are discussed below.
If you have ever taken a painkiller and wondered, how does it know where to dull the pain then this article is for you. There are many over-the-counter pain medications such as Aspirin, Ibuprofen and Naproxen, and these all produce their pain relieving effects in the same way. To discuss how painkillers work though it is important to appreciate how the body works on a molecular level, a topic known as molecular biology. A discussion of molecular biology often results in introducing some aspects of biochemistry, the study of chemical reactions that occur in the body, so some basic elements of both of these topics will be discussed.
TYPES OF PAINKILLER
There are three classes of painkiller, (i) Opiates, (ii) Opioids and (iii) Non-Steroidal Anti-Inflammatory Drugs. Opiates refer to a group of compounds which naturally occur in the poppy plant, they include Morphine, Codeine, and Thebaine. Opioids are man-made compounds that resemble Opiates. They are also effective at treating pain, and include compounds like Fentanyl, Oxycodone, and Methadone. The supply and sale of opiates and opioids is restricted since they are addictive. The final class of painkiller, NSAIDs, are available to buy over the counter.
COMMON NSAIDs
Aspirin, Ibuprofen, Naproxen are commonly used painkillers found in over the counter medication such as Advil, Nurofen, Disprin Aleve, and Brufen. These are all members of a family of drugs known as NSAIDs (Non-Steroidal Anti-Inflammatory Drugs). The molecular structure of both aspirin (left) and ibuprofen (right) is shown below.
For those of you unfamiliar with chemical structures the picture above won't make a lot of sense, but really all you need to know is that each and every chemical has its own unique structure associated with it. You can think of a chemical compound as being like a key. Just like a key each compound is unique, and interacts selectivity with it's environment. The locks in this analogy are actually large macromolecules called proteins.
CELL BIOLOGY - THE BASICS
Our bodies are composed of cells. Cells themselves are incredibly complicated, and in the same way we have organs cells have specialized substructures called organelles. It helps to think of a cell as an automated factory with different manufacturing compartments (organelles). Each compartment has its own set of sophisticated autonomous robots capable of gauging the supply and demand from the outside world, and ramping production up/down accordingly. For a cell, these sophisticated, autonomous robots are actually proteins, more specifically, proteins called enzymes.
SO - WHAT ARE ENZYMES ?
Sticking to our factory analogy, enzymes are the autonomous construction robots inside the cell. In the same way that robotic arms of a car manufacturing facility automatically cut, shape and paint car parts, enzymes work on a specific chemical compounds, biochemists called these substrates, and modify them by the addition or removal of individual atoms to make new compounds the body actually needs. In addition, in the same way a robotic arm only uses a small portion of its entire structure to perform its function, say, the delicate fingers of a larger robotic hand, the modification of substrates occurs only in a small region of the entire enzyme called the active site. The relevance of this becomes apparent later on.
Enzymes are extremely interesting molecules in their own right, with intricate moving parts, and complex structural features. It's difficult to envisage what they might look like, and in reality they have a myriad of different structures. The COX enzyme I refer to later actually looks like this in real life.
On the left is a 3D rendering of the entire enzyme molecule. It's worth pointing out that this is not an artist representation of what it might look like, but an accurate 3D model generated from X-ray images. It's similar to taking an X-ray of your arm to determine the structure of the bone underneath. This enzyme is a dimer, meaning it is composed of two identical subunits, therefore, the areas coloured red and blue represent different regions of the same enzyme molecule. Both subunits have an active site capable of interacting with NSAID molecules.
The image on the right is simply a zoomed in version of the image on the left. Here you can see a yellow coloured molecule. This is where, and roughly the orientation in which an NSAID molecule would bind. You can see how it is located in only a very small region of the enzyme, this is the active site.
Enzymes are extremely interesting molecules in their own right, with intricate moving parts, and complex structural features. It's difficult to envisage what they might look like, and in reality they have a myriad of different structures. The COX enzyme I refer to later actually looks like this in real life.
The image on the right is simply a zoomed in version of the image on the left. Here you can see a yellow coloured molecule. This is where, and roughly the orientation in which an NSAID molecule would bind. You can see how it is located in only a very small region of the enzyme, this is the active site.
SO - HOW ARE ENZYMES AND PAIN RELATED?
When a person takes a painkiller they are introducing millions of painkiller molecules, say, Ibuprofen, into the body. These molecules circulate in the blood stream looking not doing very much. However, if one of the molecules should happen to encounter a molecule of COX-2, then there's a chance they will interact. If there is an interaction between Ibuprofen and COX-2 this results in a complete shutdown of COX-2, and ultimately and a reduction in pain, here's how.
COX-2, PROSTAGLANDINS & PAIN
Pain is often the result of inflammation. For example, you strain a ligament during exercise, the muscle becomes inflamed, and increases the pressure in the surrounding tissue. Increased pressure equates to pain. The inflammation that arises as the result of an injury is the result of the COX-2 enzyme. The COX-2 enzyme is responsible for producing a series of small molecules called prostaglandins from a precursor molecule called arachidonic acid. So, yeah, we have an enzyme that makes pain - thanks evolution!
One prostaglandin in particular, prostaglandin E2, or PGE2, is responsible for generating the pain response. Aspirin, Ibuprofen, and all other NSAIDs work by inhibiting the production of PGE2. Specifically, they bind to the COX-2 enzyme, and prevent it from making PGE2. Aspirin is able to bind selectivity to COX-2 because of its 3D arrangement of atoms. Simply put, it's one of a small number of compounds that fit into active site of the enzyme. There are many potential enzymes that Aspirin could bind to, and it may interact fleetingly with many other molecules, but it is particularly well suited to binding to COX-2. This makes the interaction between Aspirin and COX-2 a targeted one. So while a molecule of Aspirin doesn't "know" where it should go, it really can interact in one place in the entire body for any long period of time. Pretty cool eh?
COX ENZYMES
So, why do we even have the COX enzyme? Well, there are actually two COX enzymes, simply called COX-1, and COX-2. They both look and behave in similar ways, you can think of them as non-identical twins, performing in similar but distinct ways, and important, looking slightly different from one another. COX-1 is often referred to as performing essential house-keeping activities, for example, it is the enzyme responsible for maintaining our stomach lining. As a result of its importance our bodies make sure to maintain a constant level of COX-1 available, this is known as constitutive expression. COX-2 on the other hand is only required as a result of injury, and so its presence is said to be induced. Once the injury is repaired COX-2 is removed by the body so as not to cause unnecessary inflammation and pain. It is actually useful for us to have means of producing pain. It prevents us from further injury. Although it is annoying!
SUMMARY
So, there you have it. Aspirin and Ibuprofen both bind selectively to the COX-2 enzyme which in turn reduces the levels of PGE2, which in turn reduces inflammation and pain. The specificity of this interaction comes from the structure if Aspirin and Ibuprofen, they bind specifically to COX-2 which is present only in the areas of injury/pain. This is why when you take a painkiller it "knows" where to go to target the pain.
As always, feel free to leave any comments or questions below, I will do my best to answer them.
REFERENCES
Pain is often the result of inflammation. For example, you strain a ligament during exercise, the muscle becomes inflamed, and increases the pressure in the surrounding tissue. Increased pressure equates to pain. The inflammation that arises as the result of an injury is the result of the COX-2 enzyme. The COX-2 enzyme is responsible for producing a series of small molecules called prostaglandins from a precursor molecule called arachidonic acid. So, yeah, we have an enzyme that makes pain - thanks evolution!
COX ENZYMES
So, why do we even have the COX enzyme? Well, there are actually two COX enzymes, simply called COX-1, and COX-2. They both look and behave in similar ways, you can think of them as non-identical twins, performing in similar but distinct ways, and important, looking slightly different from one another. COX-1 is often referred to as performing essential house-keeping activities, for example, it is the enzyme responsible for maintaining our stomach lining. As a result of its importance our bodies make sure to maintain a constant level of COX-1 available, this is known as constitutive expression. COX-2 on the other hand is only required as a result of injury, and so its presence is said to be induced. Once the injury is repaired COX-2 is removed by the body so as not to cause unnecessary inflammation and pain. It is actually useful for us to have means of producing pain. It prevents us from further injury. Although it is annoying!
SUMMARY
So, there you have it. Aspirin and Ibuprofen both bind selectively to the COX-2 enzyme which in turn reduces the levels of PGE2, which in turn reduces inflammation and pain. The specificity of this interaction comes from the structure if Aspirin and Ibuprofen, they bind specifically to COX-2 which is present only in the areas of injury/pain. This is why when you take a painkiller it "knows" where to go to target the pain.
As always, feel free to leave any comments or questions below, I will do my best to answer them.
REFERENCES
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