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.

Magnetic Gel Could Someday Treat Chronic Pain

By Pat Anson, Editor

Magnet therapy has been used for thousands of years to treat arthritis, inflammation and other chronic illnesses. Today therapeutic magnets can be found in bracelets, shoes, clothing, mattresses and dozens of other products, sold by companies that claim magnets relieve pain, improve blood flow and even flush out toxins.

It's a controversial theory and there is little science to support the medical use of magnets. One critic has even called magnet therapy “a billion-dollar boondoggle.”  

But maybe there’s something to it after all.

UCLA researchers have demonstrated that a gel-like material containing tiny magnetic particles can be used to relieve chronic pain caused by disease or injury. In a study published in the journal Advanced Materials, they say the biomechanical force of magnets can be used on damaged cells to help them heal.

"Much of mainstream modern medicine centers on using pharmaceuticals to make chemical or molecular changes inside the body to treat disease," says principal investigatorDino Di Carlo, PhD, a UCLA professor of bioengineering. "However, recent breakthroughs in the control of forces at small scales have opened up a new treatment idea -- using physical force to kick-start helpful changes inside cells. There's a long way to go, but this early work shows this path toward so-called 'mechanoceuticals' is a promising one."

Di Carlo and his colleagues used magnetic particles inside a gel to manage cell proteins that control the flow of calcium ions. The proteins are on the cell's membrane and play a role in the sensations of touch and pain. When damaged by injury or disease, these “excitable” neuron cells continually send pain signals.

"Our results show that through exploiting 'neural network homeostasis,' which is the idea of returning a biological system to a stable state, it is possible to lessen the signals of pain through the nervous system," said lead author Andy Kah Ping Tay, a recent UCLA doctoral graduate. "Ultimately, this could lead to new ways to provide therapeutic pain relief."

UCLA IMAGE

To make the magnetized gel, UCLA researchers used hyaluronic acid, a gel-like material found naturally in the spinal cord and brain. Hyaluronic hydrogel can also be produced artificially and is used in cosmetics and other beauty products as a filler and moisture barrier.

The researchers put tiny magnetic particles into the gel and then grew a type of primary neural cell -- dorsal root ganglion neurons – embedded inside the gel. In laboratory tests, they applied a magnetic field to generate a pulling force on the particles, which was transmitted through the gel to the embedded neurons.

The researchers found that the magnetically induced pulling led to an increase in calcium ions in the neurons. When they increased the magnetic force steadily over time, the neurons adapted to the continuous stimulation by reducing the signals for pain. In effect, researchers created a form of neuromodulation using magnets -- an old theory put to a new use.

In addition to treating pain, researchers say the magnetic gel could be modified with different biomaterials to treat heart disease, muscle disorders and other health conditions.

The UCLA research was funded by a New Innovator Award grant from the National Institutes of Health.

How Chronic Pain Changes Nerve Signals

By Pat Anson, Editor

Swedish researchers have developed a surprising new theory about what causes chronic nerve pain and why it is so difficult to treat.  

It has long been assumed that some sensory neurons only transmit pleasant tactile sensations, while others specialize in transmitting pain. But scientists at Karolinska Institutet have discovered that neurons that normally allow us to feel a caress or soft touch can switch roles and start signaling pain after nerve damage.

The researchers identified a small RNA molecule (microRNA) in neuron cells that regulates how touch is perceived. Levels of the molecule drop after neurons are damaged, which raises levels of a specific ion channel that makes the nerves sensitive to pain.

"Our study shows that touch-sensitive nerves switch function and start producing pain, which can explain how hypersensitivity arises," says Professor Patrik Ernfors at Karolinska Institutet's Department of Medical Biochemistry and Biophysics.

"What's interesting about our study is that we can show that the RNA molecule controls the regulation of 80 per cent of the genes that are known to be involved in nerve pain. My hope, therefore, is that microRNA-based drugs will one day be a possibility."

The research was primarily conducted on mice but also verified in tests on human tissue, where low microRNA levels could be linked to high levels of the ion channel and vice versa, suggesting that the mechanism is the same in humans. Researchers believe the study findings, published in the journal Science, could lead to more effective pain treatments   

"It's vital that we understand the mechanisms that lead to chronic nerve pain so that we can discover new methods of treatment," says Ernfors. "The pharmaceutical companies have concentrated heavily on substances that target ion channels and receptors in pain neurons, but our results show that they might have been focusing on the wrong type of neuron."

Neuropathy and chronic nerve pain are common conditions, but the drugs available to treat them have limited efficacy. One widely used medication that blocks ion channels -- gabapentin (Neurontin) – is only effective in about half of the patients who take it, according to Ernfors.