The Mystery Behind the “Granddaddy” of Medical Mysteries
How scientists, researchers, and doctors are unable to find out how general anesthesia truly functions.
A Brief Backstory
Have you ever wondered what it feels like going into surgery? The simple answer is nothing. Most times you won’t even remember what happened during your procedure. That’s all because you were probably under general anesthesia. On October 16th, 1846, the earliest form of general anesthesia was used on a patient at Massachusetts General Hospital by dentist William T.G Morton and surgeon John Warren. This marked the official date of one of the most important and mysterious healthcare advances made to date. The two men managed to demonstrate a successful loss of consciousness on a patient. Although that was the date that anesthesia was used to make a patient unconscious, it had been used by many ancient civilizations long ago to lessen the unbearable pain of surgery. Various herbs, drugs, and alcohol were used. In ancient Rome, Roman anesthetists used powdered opium in a draft of wine as their primary anesthetic. In ancient Mesopotamia, alcohol and crushed herbs were used to lessen the agonizing pain patients felt during surgery.
Putting this in simple words, anesthesia is what stops you from feeling any sensation in surgery. However, that’s not it. Thanks to advances in anesthesia over the years, if administered correctly, it also hinders one’s consciousness in the sense that they won’t be able to remember what happened during their procedure. This is known as general anesthesia.
Types of Anesthesia
General anesthesia is the most commonly used out of the three types of anesthesia and its role is to put you in a sleep-like state before surgery or other medical procedures. One is unconscious, so they don’t feel any pain whatsoever. In general anesthesia, a combination of intravenous (IV) drugs and inhaled gases (anesthetics) are used. This is primarily used for most large-scale surgical procedures for it produces the greatest effects. The next type of anesthesia is local anesthesia. Local anesthesia is used to temporarily numb a small area in your body and is used for quick surgical procedures that require less preparation and quick recovery time. An example of a surgical procedure that requires local anesthesia is repairing a broken bone by administering liquids, gels, and injections. The last type of anesthesia is regional anesthesia. It is used to numb a region of your body that requires surgery and is typically administered via injection. If one chooses to receive regional anesthesia before surgery, they can remain awake during the procedure. The most common type of regional anesthesia used in hospital settings is epidural anesthesia. Its purpose is to stop nerve signals at the spine from reaching the brain.
The Big Question
Staying on the topic of stopping nerve signals from reaching the brain, Dr. Richard Lerner, founder of Scripps Research in San Diego, CA, likes to describe anesthesia as the “Granddaddy of medical mysteries,” because although humans have used anesthesia for as long as they can remember, they can’t seem to find an answer to the question: What happens on the molecular level for someone to lose consciousness?
Before we get into the theories, we need to understand how pain works. Pain begins when nerve fibers respond to noxious stimuli. For example, when you prick your finger with something sharp, the nociceptors in your skin register this sensation. This sensation then goes to a dendrite, one of the two parts of a neuron. The signal travels through the long part of the neuron called an axon, and this cycle repeats until the signal eventually arrives at the spinal cord where it gets sent up via a nerve fiber. The type of nerve fiber that it goes by also varies depending on what type of stimuli is activated. In our scenario, it would go through the type A-delta fiber because it is a sharp sensation related pain. This fiber will carry the signal all the way to the cerebral cortex where it will get interpreted at mind-blowing speeds allowing you to react to the pain.
So now that we have a general understanding of how we interpret pain, there are 2 proposed theories that best describe how general anesthesia works. Although there are quite a few theories that try and describe how general anesthesia manages to make one lose consciousness, these two are the most compelling and are fairly similar to each other.
Theory 1
The first proposed theory is called the lipid hypothesis theory. There are two parts to this theory. The outdated lipid hypothesis and the modern lipid hypothesis.
Before we dive into the outdated lipid hypothesis theory, we need to understand a bit about the Meyer-Overton correlation. At the start of the 20th century, Hans Horst Meyer and Charles Ernest Overton independently discovered the correlation between lipid solubility and anesthetic potency (the effectiveness of anesthetics is related to how soluble they are in lipids). Meyer concluded that all chemically indifferent, fat-soluble agents would function as anesthetics. The presumed mechanism was that agents were able to act at the lipid bilayer of the cell membrane, specifically those of neurons. Later in the century, a new study showed that proteins were the likely site of action (perhaps enzymes or ion channels). They assumed that bulky and hydrophobic anesthetic molecules (nonpolar molecules that repel water molecules) accumulate inside the hydrophobic regions of the neuronal lipid membrane causing its distortion and expansion due to volume displacement. This membrane thickening alters the function of membrane ion channels, thus producing the anesthetic effect. They concluded that the chemical composition of the anesthetic wasn’t as important as the molecular volume. That is because the more space an anesthetic takes up in the cell, the greater its anesthetic effect.
This theory was the one that people believed for a while and there were also a couple of theories that were formed from this, however, they all had similar flaws that made them invalid:
- All general anesthetics induce immobilization by affecting the spinal cord functions and exert amnesic functions on the brain. According to the Meyer-Overton correlation, the anesthetic potency of a drug is directly proportional to its lipid solubility, however, many compounds don’t satisfy this rule. Some drugs were predicted to act as general anesthetics do based on their lipid solubility, however, they didn’t and only exerted the amnesic (sleep-inducing) constituent. We call these drugs nonimmobilizers. The existence of nonimmobilizers suggests that anesthetics induce different components of anesthetic effect by affecting different molecular targets.
- An increase in the chain of a homologous series of straight-chain alcohols or alkanes increases their lipid solubility, but not their anesthetic potency for it stops increasing beyond a certain cutoff length. According to the Meyer-Overton correlation, increasing the chain length of homologous series (a group of organic compounds that differ by one methylene (CH2) group) of any general anesthetic increases lipid solubility, thus producing a greater anesthetic effect. However, this is not the case in n-alcohols and n-alkanes. In n-alcohols, the chain cutoff (when the anesthetic effect disappears beyond a certain chain length) is about 13. In n-alkanes, the chain cutoff is between 6–10 depending on the species. This cutoff was first interpreted as evidence that anesthetics exert their effect by binding directly to hydrophobic pockets of well-defined volumes in proteins rather than acting on membrane lipids. As the alkyl chain (an alkane missing one hydrogen) grows, the anesthetic binds with greater affinity by filling more of the hydrophobic pocket. When the molecule is too large and isn’t able to entirely fit in the hydrophobic pocket, the binding affinity no longer increases with increasing chain length. Therefore the volume of the n-alkane chain at the cutoff length provides an estimate of the binding site volume. This provides the basis for the second theory: The Protein Synthesis Theory.
Now that we learned some of the basics of the outdated lipid hypothesis theory and why it failed, we can move on to the modern lipid hypothesis theory.
The modern version of the lipid hypothesis theory states that an anesthetic effect of a general anesthetic occurs if the solubilization in the bilayer causes a redistribution of membrane lateral pressures. Bilayer membranes are characterized by large lateral stresses that vary with depth within the membrane. Each bilayer membrane has a separate profile of how lateral pressures are distributed within it. According to the modern lipid hypothesis, a change in the membrane lateral pressure profile (the distribution of lateral stresses across the width of the lipid bilayer) shifts the conformational equilibrium of certain membrane proteins known to be affected by clinical concentrations of anesthetics such as ligand-gated ion channels. This mechanism is also nonspecific because the potency of the anesthetic is determined not by its actual chemical structure, but by the orientation of its bonds within the bilayer. If channel opening increases the cross-sectional area of the protein more near the aqueous interface than in the middle of the bilayer, then the anesthetic-induced increase in lateral pressure near the interface will shift the protein conformational equilibrium to favor the closed state, since channel opening will require greater work against this higher pressure. This is the first hypothesis that provided a detailed mechanistic (relating to theories that explain phenomena in purely physical and deterministic terms) and thermodynamic (relationship between heat and other forms of energy) understanding of anesthesia, instead of only correlations of potency with structural or thermodynamic properties.
Theory 2
The second theory is called the membrane protein hypothesis. It came about in the 1980s and is quite similar to the lipid hypothesis theory. It states that Anesthetics could bind to proteins in the membranes of neurons. Researchers have been able to discover various anesthetics binding to proteins, for that is how most drugs work, but it didn’t explain what the anesthetics were doing when they were bound. When the researchers at Scripps Research Florida campus exposed these cells with chloroform and watched them under a powerful microscope. They realized that the lipid clusters went from tightly condensed into very disoriented structures. You can think of it as an expansion of billiard balls after the first strike. As this happened, the lipid cluster leaked out contents, one of which was a PLD2 enzyme. The researchers then tagged this enzyme with a fluorescent chemical so that they could see where it went. Upon doing so, they realized that once on the loose, PLD2 heads over to a protein called TREK 1. Once there, it binds to TREK 1 and turns it on, causing it to open up and release positively charged potassium. As nerve cells need a certain balance of charged particles to fire out signals, the increased amounts of positively charged potassium disrupt the nerves causing them to malfunction. This prevents the nerve from firing neurons, therefore, leading one to lose sensation and consciousness.
In conclusion, although we think we have cracked the code when it comes to how anesthesia works on the molecular level, scientists still aren’t sure why this was implemented by nature. Obviously, it didn’t evolve so that surgeons could use this as a tool to ease surgery for the patient. Further research ought to shed light on why our neurons do this billiard ball mechanism. It could also help scientists better understand how neurons work and find treatments for nervous system disorders. However, as we are continuously developing new technologies, it won’t be long until we find the answer to that question as well.
I had a lot of fun researching and writing about this topic, however, I noticed that there aren’t many easily accessible resources online because some of the resources require money to access. I feel as if they should be free for all to read and obtain knowledge from. However, if you are interested in this topic, I linked the websites and videos I used to research topics in this article. They are all free and are user friendly so feel free to check them out. :)
