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by Rose Liu

art by Marcus Tian

They did surgery on a grape. What? Well, scientists may now be sedating them too.

Sedation—what is it? Remember getting your wisdom teeth plucked out? When did you lose your memory? Counting backwards from ten… nine… eight… and zzzzz, you’re asleep. You wake up to find very bloated cheeks, four missing teeth (ow), and a recording of your delirious rambling from your friends (severe ow). This lack of pain and memory is caused by anesthesia—a medical practice that induces a temporary loss of sensation or consciousness [1]. Many patients cannot go without the pain relief (and memory loss) provided by anesthesia: could you imagine what wisdom teeth removal would feel like without it?

Remarkably, recent studies have shown that plants under anesthesia may exhibit the same effects at the cellular level as humans [2]. By investigating how plants respond to anesthetics, scientists can develop novel anesthetic agents without experimenting on human subjects.

Anesthesia: Loss of Sensation

No, mom, nothing I said post-tooth-removal was true. No, those were not bottled-up secrets…. is a scenario we pray won’t happen after surgery. These (socially awkward) post-op ramblings are a famous side effect of anesthesia. To reduce pain and sometimes consciousness, anesthesia is administered pre-surgery [2]. This novel concept was only developed in 1846. Since then, more than 60,000 people nationally undergo anesthesia every day for surgeries [3]. Anesthesia in the nineteenth century was crude and often dangerous, involving the use of substances such as chloroform that could cause severe side effects and even death. Thank god we aren’t given chloroform for our root canals!

There are three types of anesthetics: local, general, and regional anesthesia [4]. While local anesthesia is usually limited to a specific area, general anesthesia may cause loss of consciousness entirely [4]. For example, neurosurgery requires general anesthesia and root canals use local anesthetics [5]. Between general and local anesthesia is regional anesthesia. Regional anesthesia, which does not make a patient lose consciousness, is a broader term for local anesthesia that is applied to a larger region of the body than local [4]. For instance, epidural injections are a form of regional anesthesia used to numb the pelvic area during childbirth when one undergoes labor [6].

To achieve operating conditions, anesthesiologists move the patient through three components of anesthesia: sedation (relaxation), amnesia (memory loss of the procedure), and analgesia (pain relief) [4]. This mixture of drugs eventually works to interrupt neural pathways, ultimately slowing down communication within the human body. Anesthesia depresses excitatory neurons, which strengthen pain signals, and increases inhibitory neurons, which suppress pain signals [4].

Model organisms have been used extensively in research on the effects of anesthesia, which has helped to improve our understanding of its action mechanisms and potential risks.

Anesthesia Studies: Plants as Model Organisms

Plants are more than just pretty faces in the botanical world—or, maybe they’re not. Plants have recently become model organisms for anesthetic studies. Model organisms are non-human species used in scientific research to display and understand biological processes and phenomena [7]. Observations and theories originating from research involving these experimental organisms can often be extrapolated to more complex species, including humans [7]. For example, Swiss mice and primates are common model organisms scientists experiment on because they have similar cellular processes to those found in humans [8]. So, if plants share a biological process with humans, could results from studying those processes also be applied to humans?

This experimental opportunity between plants and anesthesia can be attributed to the neuron’s most fundamental trait: its ability to generate action potentials. Despite plants lacking the same specialized neurons humans have, they are still able to generate action potentials for their green way of life.

The Spark of Life

Zip! Zip… Zip! Our bodies conduct biological messages through a sequence of small electric signals called an action potential [9]. The action potential is a rapid change in the ratio of certain ions across a membrane, which temporarily reverses the membrane's electric polarization, resulting in a redistribution of positive and negative electrical charge across the cell. This change in polarization then allows cells to communicate with each other and send messages throughout the body [9].

So, when you are engaged in a physically demanding activity like running, your brain sends these signals to your muscles through nerves, ultimately causing more action potentials to be generated, resulting in increased speed [9]. This demand occurs across all bodies of life. For example, if you visit the Barnard Greenhouse, you’ll find the mimosa, a peculiar plant that folds its leaves inward or droops if you touch it hard enough. Here, its mechanoreceptors detect the human touch and fire action potentials, which send messages that eventually cause the mimosa to droop [10].

A stimulus, such as the one received by the mimosa when it is touched, must increase a cell's charge to the threshold of -50 mV for an action potential to be initiated—causing depolarization, where positively-charged sodium ions make the neuron more positively charged [9]. This influx of positive ions allows the bodily messages to be transmitted, resulting in the folding of the mimosa leaves. Repolarization occurs when positively-charged potassium ions exit the neuron, resulting in a net negative charge (-85 mV) within the neuron. This is followed by a refractory period, where the neuron cannot initiate another action potential until it returns to its resting state at -70 mV [9].

Excitatory currents prompt one neuron to share information with another through an action potential, while inhibitory currents reduce the probability that such a transfer will take place [9]. Imagine you're at a party and you have some important news to share with a group of people. Just like you might use a messenger to spread the word, in our bodies, excitatory neurotransmitters act as chemical messengers, carrying crucial information between neurons. After a neuron fires an action potential, it releases neurotransmitters that travel across the synaptic gap to a neighboring neuron, triggering another action potential [9]. In doing so, our brains function properly and stay in communication with themselves. So, the next time you're at a party, remember the power of chemical messengers and the importance of communication—even at the cellular level.

However, not all neurotransmitters lead to the production of an action potential. In addition to excitatory receptors like those that bind to glutamate, inhibitory receptors such as gamma-aminobutyric acid (GABA) receptors also play a critical role in regulating nerve signaling by reducing the activity of neurons [9]. Action potentials are important because they can either inhibit or promote movement.

Let’s say you (21+) try a different kind of mimosa: a champagne and citrusy type. Drink too much and you can credit your sluggish movements to the activation of inhibitory receptors, which reduces the ability of your nerves to transmit signals [11].

While excessive consumption of champagne and citrusy mimosas can lead to sluggish movements, it is interesting to note that action potentials, which are responsible for nerve transmission, are not exclusive to humans and animals but also occur in plants, as demonstrated by studies on the Venus flytrap [10]. In 2017, Yokawa and collaborators demonstrated for the first time how bioelectricity and action potentials take place not only in humans and animals, but also in plants. Their study revealed that action potentials are necessary to close the trap and initiate the digestive processes of this carnivorous plant species [10].

Typically, in carnivorous plants like the Venus flytrap, action potentials play a key role in the rapid movement of their leaves to capture prey [12]. When an insect touches the sensory hairs on the plant's leaves, a surge of positive ions like potassium and calcium flood the cell, sparking an electrical charge that triggers an action potential. The action potential races through the plant's vascular system, triggering the rapid closure of the leaf and prey capture [12].

These scientists have shown that, after administering anesthetics, closure of the Venus flytrap is prevented. This happens due to a delay in the production of action potentials, explaining why anesthesia has a similar effect on plants as in humans [10]. And so, plants may bloom new discoveries about the underlying mechanism of anesthesia.

In modern medicine, however, the molecular mechanism behind general anesthetics remains unclear. Currently, there are two theories for anesthetic action: the modern lipid hypothesis and the membrane protein hypothesis [13].

The Fat Truth

Beyond just your kitchen’s olive oil, lipids are found everywhere in the human body and play an important role in cells, as they make up the cell membrane. The cell membrane is made up of phospholipids, which are a group of lipid molecules that have hydrophobic (water-fearing) tails and hydrophilic (water-loving) heads [9]. The fluidity of cellular membranes is determined by the type of fats that make up the phospholipids because the length and saturation of these fats affect how tightly packed they are, which in turn affects how easily they can move around and interact with other molecules in the membrane. Membrane fluidity is important because it affects the permeability and functionality of the membrane proteins and their interactions with other molecules. The fluidity of lipids can impact the ease with which chemicals can cross the barrier, ultimately impacting cellular function and signaling. The hydrophobic and hydrophilic tails of the phospholipid bilayer act as a barrier, controlling the flow of substances into and out of the cell [9].

The lipid hypothesis of anesthesia suggests that anesthetic drugs work by altering the physical properties of lipid membranes in the central nervous system [13]. According to this hypothesis, local anesthetic drugs act by altering the fluidity and permeability of neuronal cell membranes, leading to changes in the biophysical properties of the lipid bilayer. This disrupts the normal functioning of ion channels and neurotransmitter receptors, leading to a reduction in the excitability of nerve cells because the rigid structure of the phospholipid membrane is harder to penetrate. Thus, fewer action potentials are formed, meaning that the body receives and communicates less information. Together, this reduction in excitability is thought to result in the loss of consciousness and absence of pain perception associated with general anesthesia [13].

However, it is still up for debate whether this hypothesis can explain the mechanisms behind both general and local anesthetics. Currently, the lipid hypothesis seems to only be true with local anesthetics [14]. A study conducted by Herold and collaborators disproved that clinical levels of general anesthesia have effects on lipid bilayer membranes, suggesting that general anesthetics directly interact with membrane proteins without altering lipid bilayer properties at clinically relevant concentrations [14].

Interestingly, another group of scientists found that local and regional anesthesia does have an effect on lipid bilayer membranes. Their study revealed that when a local anesthetic is administered, it needs to travel through barriers made of fat. These anesthetics interact with the fat hydrophobically to make them more fluid which affects how well channels and proteins in the membranes work [15].

The relationship between anesthetics and membrane fluidity can also be studied by subjecting the lipids in the lab to different pressures. Generally, lipids are relatively flexible and fluid at low pressures, but their behavior can change dramatically at high pressures—sometimes becoming drastically more rigid or more fluid [16]. Studies have shown that high pressure can reverse the action of general anesthetics. The changes in pressure lead to changes in the fluidity of the lipid bilayer, which impacts the distribution and mobility of anesthetic molecules [16].

Though there is a clear and definite relationship between pressure and general anesthesia, further research is necessary to examine the direct effects of pressure on lipid membranes.

Anesthetics and Proteins: Investigating the Link

While the lipid hypothesis argues that anesthetics are directly acting on the lipid bilayer, the protein hypothesis states that anesthetics do not affect the bilayer directly and instead affect proteins [17]. The protein hypothesis suggests that the mechanism of action for general anesthetic drugs is related to their interaction with specific proteins in the central nervous system [17].

This hypothesis was developed after scientists discovered that certain anesthetic drugs interact with specific proteins, and that mutations in these proteins can alter anesthetic sensitivity [17]. Some proteins that have been identified as potential targets of anesthetics include GABA receptors. According to this hypothesis, anesthetic drugs act by changing the structure of specific proteins, thus altering their function. This leads to changes in neural signaling and synaptic transmission, which can result in a loss of consciousness or other changes in behavior [17].

In the 1950s, researchers identified the GABA receptor, which is a ligand-gated ion channel that mediates inhibitory neurotransmission, as a key target of anesthetic drugs like barbiturates and benzodiazepines [18].

Barbiturates and benzodiazepines are two classes of drugs commonly used as anesthetics [19]. They exert their effects in the body by binding to specific sites on the GABA-A receptor. The GABA-A receptor is composed of five protein subunits. The binding sites for barbiturates and benzodiazepines are located on different subunits of the receptor. Where these anesthetics bind determines their specific effects on the cell. When barbiturates bind to the GABA-A receptor, they increase the duration of channel opening, thereby enhancing the effects of GABA and increasing the flow of ions into the neuron. This results in a decrease in neuronal excitability and an increase in the overall inhibition of the brain, leading to sedation and anesthesia [19].

Similarly, when benzodiazepines bind to the GABA-A receptor, they enhance the effects of GABA by increasing the frequency of channel openings, again leading to increased chloride ion flow and neuronal inhibition [19]. In other words, they modulate the activity of the receptor in the presence of GABA [19].

It is now understood that in addition to lipid mechanisms, which can contribute to the action of anesthetic drugs, there are also protein-mediated mechanisms. Both of these hypotheses may be correct and neither hypothesis contradicts the other [14].

Leaf the Pain Away

Using plants as a model organism for anesthesia research can help scientists better understand the lipid and protein hypotheses of anesthesia by providing a simple and accessible system to study the effects of anesthetic drugs on cellular membranes and proteins.

Plants are eukaryotes, or organisms composed of complex cells that have a nucleus and membrane-bound organelles [9]. Plants have many similar cellular and molecular processes as animals, including lipid bilayer membranes. These organisms also have proteins, like GABA-A, which are involved in ion transport and signal transduction. Plants are often considered simple and accessible research models compared to animal models, such as humans, due to their relatively straightforward genetics and physiology, as well as their ability to easily grow and be manipulated in laboratory settings. While animal models offer important insight into complex biological systems, they can also be more difficult and expensive to work with, making plant models an attractive alternative for certain types of research [9].

By studying the effects of anesthetic drugs on plant cells and tissues, researchers can gain insight into how these drugs interact with lipid and protein targets, and how these interactions lead to changes in cellular function. This can provide valuable information about the mechanism of action of anesthetic drugs, and help us understand whether the lipid and protein hypotheses of anesthesia coexist.

Recently, researchers like Ken Yokawa of the Kitami Institute of Technology have demonstrated that plants and humans share similarities when it comes to anesthesia. His 2017 study revealed that, just like in animals, anesthetics used at appropriate concentrations block action potentials and immobilize organs via effects on action potentials in plants [10]. In order to investigate the effects of anesthetics on plants, the researchers examined endocytic vesicle recycling, which is the way cells repurpose lipids and proteins into their cellular functions. Endocytic vesicle recycling was studied in relation to anesthetics as a way to investigate the effects of anesthetics on the repurposing of lipids and proteins in cellular functions, in line with their hypothesis that anesthetics can affect cellular processes and signaling pathways in plants. For this, Yokawa and associates used a fluorescent dye uptake assay and observed the internalization of the dye in the presence and absence of anesthetics [10]. Fluorescent dye uptake assay measures the viability of cells in a culture or tissue sample, as live cells have intact cell membranes that exclude the fluorescent dye, while dead or damaged cells have compromised cell membranes that allow these dyes to enter and fluoresce [10]. Through this assay, the researchers were able to determine that anesthetics affect reactive oxygen species (ROS) homeostasis in plant cells, which is important for regulating cellular processes and preventing oxidative stress-induced damage to cellular components such as proteins and lipids [10]. In low concentrations, ROS play important roles in cell signaling, however, excessive ROS production can cause oxidative stress and damage cellular macromolecules, including proteins and lipids [20]. Yokawa and collaborators’ observations of these ROS molecular mechanisms could direct the future of general anesthesia in understanding the model of plants [10].

The Yokawa study did not stop at discovering how anesthetics impact plant cells. They also uncovered something truly remarkable—that anesthetics can have a profound effect on plant movement [10]. By using various anesthetics like diethyl ether, chloroform, and isoflurane, researchers found that plants such as the Venus flytrap (Dionaea muscipula), Mimosa pudica, and Arabidopsis thaliana were significantly inhibited in their movements. What's even more interesting is that their experiments with the Venus flytrap revealed how anesthetics block action potentials in plants. Using microelectrode recordings, they found that anesthetics prevented the generation of these electrical signals, which are vital for transmitting information and regulating physiological processes in plants [10]. So why are plants so sensitive to anesthetics? As it turns out, they use similar critical proteins as possible targets of anesthetics in animals and humans, including glutamate and GABA receptors. This groundbreaking discovery reveals that there's much more to plant behavior and cellular processes than we previously thought.

Sprouting New Futures

The molecular mechanisms of anesthesia are complex and multifaceted, involving a wide range of cellular processes and signaling pathways.

Just as each individual has their unique genome, each anesthesia procedure must also be tailored to the specific needs of the patient. It's like a garden where every plant needs different care and attention to grow. So, to research’s future, let's keep sprouting new ideas and discoveries in anesthesia, and maybe one day we'll have the perfect anesthesia cocktail for each and every one of us. Until then, let's root for smooth sailing and sweet dreams during our next surgery.


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