Going Under

October 15, 2019

Written by: Sarah Reitz


Given that general anesthetics are used in over 300 million surgeries each year,1 it is easy to take these drugs for granted. However, anesthetics were not used in hospital settings until the mid-1800s. Prior to this time, surgeries were used as an absolute last resort since the patient was awake and able to feel everything during a procedure. While this was excruciating for the patients, it also caused problems for the surgeons who had to perform procedures as quickly as possible to minimize pain. As you can probably imagine, rushing through surgeries doesn’t leave much time for accuracy or precision. As a result, positive surgical outcomes were oftentimes not the case.

The discovery of general anesthetics, which cause rapid and reversible unconsciousness, immobility, and analgesia (or pain relief), revolutionized medicine. Surgeons could now accurately — and safely — perform delicate surgeries all while patients were blissfully unconscious. However, despite being used for the past 170+ years, we still don’t fully understand how anesthetics actually produce this state of unconsciousness. This is especially important for the small percentage, yet still significant number, of patients that experience adverse reactions to anesthesia each year. These reactions include intraoperative awareness, delayed emergence from anesthesia, and cognitive impairments following surgery.2-4 But before we can prevent these reactions from occurring, we first need to understand exactly how anesthetics produce unconsciousness in the first place.

So why don’t we know how such commonly used drugs actually produce their effects? Part of the reason is due to their chemical structure. Many times, there are a few core similarities in the chemical structures of a class of drugs that give researchers hints as to how the drugs work and also allow them to predict which other drugs may have similar effects. However, the chemical structures of general anesthetics are incredibly diverse (Figure 1), making this challenging.

Anesthetic Structures
Figure 1: The chemical structures of many general anesthetics are diverse, ranging from the single molecule anesthetic xenon to the more complex structure of dexmedetomidine. The lack of any obvious similarities across all anesthetics complicates our understanding of how they produce unconsciousness. Created with BioRender

Since there are no obvious structural similarities that point towards a mechanism, scientists thought that maybe this diverse class of drugs all act on the same class of receptors (proteins that respond to a specific stimulus or molecule) in the brain to produce this common endpoint of unconsciousness. However, many studies since then have shown that while dozens of these proteins are affected by various anesthetics, there is no known single receptor that is affected by all anesthetics.5-7 Since it is clear there is not a single protein responsible for producing unconsciousness, researchers next hypothesized that perhaps instead of acting on identical proteins in the brain, anesthetics actually act on a variety of proteins at various points along a common neural pathway that ultimately results in the same end effect of unconsciousness. But what pathway?

When patients are anesthetized, oftentimes the anesthesiologist will tell them that they will be “drifting off to sleep” or “put to sleep”. While there are obvious differences between sleep and anesthesia (you definitely would not want to perform surgery on a sleeping person!), sleep is also a reversible state of unconsciousness controlled by the brain. Scientists thought that maybe anesthetics work by hijacking the brain’s natural sleep and arousal pathways at different points to produce this unnatural form of unconsciousness.

Sleep and wake are controlled by groups of neurons that are spread across the brain. Sleep-active nuclei, as their name suggests, are groups of neurons that become active when we sleep or are sleepy and cause us to fall asleep. On the other hand, wake-active nuclei promote wakefulness and cause us to be more alert. When we sleep, the sleep-active nuclei inhibit the wake-active neurons, preventing them from promoting wakefulness (Figure 2). On the other hand, when we are awake the wake-active neurons promote wakefulness in part by inhibiting the sleep-active neurons to prevent us from falling asleep. These two circuits form a “switch” of sorts, which can be flipped to either produce sleep or wakefulness.

MolPharm NREM Sleep (2)
Figure 2: Sleep and arousal promoting pathways are spread throughout the brain. Sleep-promoting regions (shown in red) promote sleep by inhibiting (red arrows) the wake-promoting neurons of the brain (shown in green). When you are awake, the “switch” flips and the wake-promoting neurons become active, inhibiting the sleep-promoting neurons, preventing them from producing sleep.

In the past two decades, more and more research has revealed that anesthetics act on many of the key nuclei in these sleep and arousal pathways. Many anesthetics, including isoflurane, propofol, and dexmedetomidine, inhibit wake-promoting regions like the locus coeruleus and the tuberomammillary nucleus.8-11 These findings were interesting, but not too surprising since anesthetics tend to broadly inhibit many regions of the brain. However, what did surprise scientists was the finding that anesthetics actually activate sleep-promoting neurons! Work done right here at Penn showed that isoflurane, an inhaled anesthetic, activates neurons in the ventrolateral preoptic area (VLPO), a major sleep-promoting region of the brain.12 Even more interesting is the fact that this activation seems to be specific for sleep-promoting VLPO neurons, since neighboring, non-sleep-promoting neurons in the same region were inhibited by the anesthetic. Since then, numerous other anesthetics have also been shown to activate VLPO neurons,13,14 suggesting that activation of sleep-promoting neurons may be a common mechanism for how anesthetics produce unconsciousness.

While evidence continues to suggest the brain’s natural sleep and arousal pathways are key players in anesthetic-induced unconsciousness, there is still much to learn. We know there are other sleep-promoting nuclei in the brain besides the VLPO. Do anesthetics also activate these regions? Additionally, how do anesthetics activate these sleep-promoting neurons, and what is it about these cells that set them apart from other neurons in the brain that aren’t activated by anesthetics? It is also highly likely that activation of sleep-promoting neurons is not the sole cause of anesthetic unconsciousness (after all, anesthesia is not identical to just being asleep). But what are these other key players in producing unconsciousness?

As we continue to learn more about how anesthetics actually produce unconsciousness, we will hopefully be able to better predict who will experience adverse reactions and prevent them from occurring. Additionally, one day we might be able to design better, more specific anesthetics that will produce unconsciousness without the risk of any other side effects. Hopefully one day we will be able to fully understand these drugs that are so commonly used throughout the world.


Image References:

Cover image by Sasin Tipchai via Pixabay, https://pixabay.com/photos/surgery-hospital-doctor-care-1807541/

Figure 1 images via Wikimedia Commons, created with BioRender

Figure 2 created with BioRender




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