How Anesthesia Drugs Work in the Brain

By Dr. Adam Hines   

Over 350 million surgeries are performed globally each year. For most of us, it’s likely at some point in our lives we’ll have to undergo a procedure that needs general anaesthesia.

Even though it is one of the safest medical practices, we still don’t have a complete, thorough understanding of precisely how anaesthetic drugs work in the brain. In fact, it has largely remained a mystery since general anaesthesia was introduced into medicine over 180 years ago.

Our study published in The Journal of Neuroscience provides new clues on the intricacies of the process. General anaesthetic drugs seem to only affect specific parts of the brain responsible for keeping us alert and awake.

In a study using fruit flies, we found a potential way that allows anaesthetic drugs to interact with specific types of neurons (brain cells), and it’s all to do with proteins. Your brain has around 86 billion neurons and not all of them are the same – it’s these differences that allow general anaesthesia to be effective.

To be clear, we’re not completely in the dark on how anaesthetic drugs affect us. We know why general anaesthetics are able to make us lose consciousness so quickly, thanks to a landmark discovery made in 1994.

But to better understand the fine details, we first have to look to the minute differences between the cells in our brains. Broadly speaking, there are two main categories of neurons in the brain.

The first are what we call “excitatory” neurons, generally responsible for keeping us alert and awake. The second are “inhibitory” neurons – their job is to regulate and control the excitatory ones.

In our day-to-day lives, excitatory and inhibitory neurons are constantly working and balancing one another.

When we fall asleep, there are inhibitory neurons in the brain that “silence” the excitatory ones keeping us awake. This happens gradually over time, which is why you may feel progressively more tired through the day.

General anaesthetics speed up this process by directly silencing these excitatory neurons without any action from the inhibitory ones. This is why your anaesthetist will tell you that they’ll “put you to sleep” for the procedure: it’s essentially the same process.

A Different Kind of Sleep

While we know why anaesthetics put us to sleep, the question then becomes: “Why do we stay asleep during surgery?” If you went to bed tonight, fell asleep and somebody tried to do surgery on you, you’d wake up with quite a shock.

To date, there is no strong consensus in the field as to why general anaesthesia causes people to remain unconscious during surgery.

Over the last couple of decades, researchers have proposed several potential explanations, but they all seem to point to one root cause. Neurons stop talking to each other when exposed to general anaesthetics.

While the idea of “cells talking to each other” may sound a little strange, it’s a fundamental concept in neuroscience. Without this communication, our brains wouldn’t be able to function at all. And it allows the brain to know what’s happening throughout the body.

Our new study shows that general anaesthetics appear to stop excitatory neurons from communicating, but not inhibitory ones. This concept isn’t new, but we found some compelling evidence as to why only excitatory neurons are affected.

For neurons to communicate, proteins have to get involved. One of the jobs these proteins have is to get neurons to release molecules called neurotransmitters. These chemical messengers are what gets signals across from one neuron to another: dopamine, adrenaline and serotonin are all neurotransmitters, for example.

We found that general anaesthetics impair the ability of these proteins to release neurotransmitters, but only in excitatory neurons. To test this, we used Drosophila melanogaster fruit flies and super resolution microscopy to directly see what effects a general anaesthetic was having on these proteins at a molecular scale.

Part of what makes excitatory and inhibitory neurons different from each other is that they express different types of the same protein. This is kind of like having two cars of the same make and model, but one is green and has a sports package, while the other is just standard and red. They both do the same thing, but one’s just a little bit different.

Neurotransmitter release is a complex process involving lots of different proteins. If one piece of the puzzle isn’t exactly right, then general anaesthetics won’t be able to do their job.

As a next research step, we will need to figure out which piece of the puzzle is different, to understand why general anaesthetics only stop excitatory communication.

Ultimately, our results hint that the drugs used in general anaesthetics cause massive global inhibition in the brain. By silencing excitability in two ways, these drugs put us to sleep and keep it that way.

Adam Hines, PhD, is a Research Fellow at Queensland Brain Institute at The University of Queensland in Australia. His research focuses on combining neuroscience and artificial intelligence to develop “bio-inspired robotics.”

This article originally appeared in The Conversation and is republished with permission.

What Pain Patients Should Know About the GABA Neurotransmitter

By Forest Tennant, PNN Columnist

“GABA” is short for the neurotransmitter, gamma aminobutyric acid. GABA is the natural (endogenous) biochemical substance in the brain, spinal cord, and all nerves that control electrical conduction.

Without proper GABA function, we experience pain. New research also shows that low levels of GABA make it harder to keep negative emotions such as fear, worry, anxiety and depression in check. 

All Intractable Pain Syndrome (IPS) patients have nerve damage somewhere in their brain, spinal cord, or nerves. Consequently, IPS patients will either need extra GABA or a GABA surrogate to force damaged nerve tissue to correctly function and relieve pain. 

GABA Surrogates

Without realizing it, you may already be taking a GABA surrogate. And you may have found that your pain gets worse without one. Here are the most effective prescription surrogates:

• Gabapentin (Neurontin)

• Carisoprodol (Soma)

• Diazepam (Valium)

• Alprazolam (Xanax)

• Lorazepam (Ativan)

There are also herbs and amino acids available without a prescription that can be used as GABA surrogates:

• Valerian root

• Ashwagandha

• Taurine

• Brahmi

• Bacopa

Glutamine: GABA’s Precursor

The term “precursor” refers to nutrients or raw material that help make a neurotransmitter. Glutamine is the precursor of GABA. A dose of 2000 mg or more of glutamine a day when taken on an empty stomach with vitamin B6 (2mg or more), will increase your natural level of GABA and probably reduce your pain levels. 

Pure GABA is available as a tablet, capsule or in sublingual (under-the tongue) form in most health food stores or online. Unfortunately, when swallowed in tablet or capsule form, GABA may be digested just like food or fail to cross the blood-brain barrier, and be rendered ineffective.

But sublingual GABA is well absorbed by the body and should be given a thorough trial by every person with IPS. You can take 100 to 300mg sublingual GABA to treat pain flares, or 100 to 200mg of GABA simultaneously with an opioid medication or GABA surrogate for added pain relief.

Forest Tennant is retired from clinical practice but continues his research on intractable pain and arachnoiditis. This column is adapted from newsletters recently issued by the IPS Research and Education Project of the Tennant Foundation. Readers interested in subscribing to the newsletter can sign up by clicking here.

The Tennant Foundation gives financial support to Pain News Network and sponsors PNN’s Patient Resources section.    

Why Pain Is Not ‘All in Your Head’

By Gabriella Kelly-Davies, PNN Columnist

Anyone who lives with chronic pain knows it can affect their emotions. Every morning when I wake with a migraine, I feel a sense of doom. My heart races and I panic about how I will cope with everything that lies ahead of me that day — the meetings, deadlines and responsibilities, not to mention family and social commitments that often end up taking a back seat as I scramble to find ways of simplifying my day.

After decades of living with chronic migraine, I now know these emotions intensify my experience of pain. Having said this, I know it is not “all in my head” as some might claim, but part of a complex interaction between my emotions and the way my central nervous system incorrectly processes pain signals.

Exciting new Australian research using sophisticated brain imaging is shedding new light on what happens at an emotional level for people living with chronic pain.

Chemical “messengers” known as neurotransmitters facilitate communication between brain cells. Some neurotransmitters are inhibitory, helping to dial down our emotions, while others are excitatory and increase the intensity of emotions. A molecule known as γ-aminobutyric acid or GABA is the main inhibitory neurotransmitter.

Neuroscientist and psychologist Sylvia Gustin, PhD, discovered that GABA levels are lower in people with chronic pain and this affects their ability to regulate their emotions. The link between lower levels of GABA and chronic pain had been shown in animal studies, but Gustin’s research, recently published in the European Journal of Pain, is the first time it has been demonstrated in humans.

“A decrease in GABA means our brain cells can no longer communicate with each other properly,” explained Gustin, an associate professor at the University of Sydney’s School of Psychology. “When there’s a decrease in GABA, it makes it harder to keep emotions such as fear, worry, anxiety and depression in check.”

Gustin’s research shows there’s a physical change in the central nervous system that helps explain the roller coaster of emotions people living with pain often experience.

“If you live with chronic pain, it’s important to remember it’s not you -- there’s something physically happening to your brain. We don’t yet know why this happens, but we’re working on finding solutions on how to change it,” Gustin told me.

Her research confirms that chronic pain, which affects one in five people worldwide, is more than just an uncomfortable sensation. “It can affect our feelings, beliefs and the way we are,” she says. “Almost half the people living with chronic pain also experience major anxiety and depression disorders.”

GABA is not the only neurotransmitter that behaves differently in people living with chronic pain. In an earlier study, Gustin and her colleagues found levels of the main excitatory neurotransmitter in the central nervous system – glutamate -- are also lower in people with chronic pain. Lower glutamate levels are linked to increased feelings of fear, worry and negative thinking. They disrupt how brain cells talk to each other, affecting the ability to feel positive emotions such as happiness, motivation and confidence.

“My research results are reassuring for people living with pain because they show that physical changes in the brain are contributing to anxiety and depression and it’s not a person’s fault they struggle with these emotions,” Gustin said.

Her research team recently developed and tested an online recovery program that teaches people skills to help modify negative emotions such as fear, worry, anxiety and depression. The program helps to address the neurotransmitter disruption in chronic pain.

“Online programs offer hope to people living with disabilities or those in rural and remote communities who often struggle to access pain management services,” she said. “Online programs are also ideal during COVID-19 lockdowns.

“We know that chronic pain is always present, and we can’t get rid of it. But we can change the way we experience it by learning new skills. Like all skills, it takes practice to master it, but we hope it will offer another tool for people to change the way they experience pain.”

Gustin says preliminary results of this research, which will be published in a few months, are encouraging. Several organizations, including Australia’s National Health and Medical Research Council and Medical Research Future Fund, the International Association for the Study of Pain (IASP) and the U.S. Department of Defense, are helping to fund her work. To learn more about this research, click here.

Gabriella Kelly-Davies lives with chronic migraine.  She is the author of “Breaking Through the Pain Barrier,” a biography of trailblazing Australian pain specialist Dr. Michael Cousins. Gabriella is President of Life Stories Australia Association and founder of Share your life story.