‘Pain switch’ could lead to a new generation of anaesthetics

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Neuron cells in the central amygdala of a mouse brain. Red, magenta and yellow cells (but not green or blue) are parts of a collection of neurons called the CeAga that has potent pain-suppression abilities
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Scientists claim to have found a small area of the brain in mice that can turn off their sense of pain like a light switch. 

US researchers say the amygdala, a small almond-shaped cluster of neurons located in each side of the brain, can turn off multiple parts of the brain that process pain.  

Beams of light activate a set of neurons in the amygdala, called ‘CeAga’ neurons, which inhibit ‘pain-promotion centres’ in the brain, they say.

In experiments, activating the CeAga neurons dramatically reduced signs of discomfort in mice who had received a mild pain stimulus.

While mice have a relatively large central amygdala compared to humans, it’s likely humans have a similar system for controlling pain.

The discovery could result in the creation of a new wave of pain-relieving drugs for humans. 

Neuron cells in the central amygdala of a mouse brain. Red, magenta and yellow cells (but not green or blue) are parts of a collection of neurons called the CeAga that has potent pain-suppression abilities

‘Pain is a complicated brain response,’ said study author Professor Fan Wang of Duke University in Durham, North Carolina, the US. 

‘It involves sensory discrimination, emotion, and autonomic – involuntary nervous system – responses. 

‘Treating pain by dampening all of these brain processes in many areas is very difficult to achieve. 

‘But activating a key node that naturally sends inhibitory signals to these pain-processing regions would be more robust.’ 

Professor Wang said most of the previous studies have focused on which regions are turned on by pain. 

‘People do believe there is a central place to relieve pain, that’s why placebos work,’ she said. 

‘The question is where in the brain is the centre that can turn off pain.  

The amygdala, shown here in red, is is the centre for emotions, emotional behaviour, and motivation. Humans have two amygdala - one in each temporal lobe of the brain

The amygdala, shown here in red, is is the centre for emotions, emotional behaviour, and motivation. Humans have two amygdala – one in each temporal lobe of the brain

‘But there are so many regions processing pain, you’d have to turn them all off to stop pain. Whereas this one centre can turn off the pain by itself.’

The amygdala is located in an area where few people would have thought to look for an anti-pain centre, the research team claim. 

WHAT IS THE AMYGDALA? 

The amygdala is an almond-shaped structure in the brain.

Humans have two amygdala – one in each temporal lobe of the brain.

Amygdalae are each formed of a cluster of nuclei – a collection of neurons, or nerve cells. 

Each amygdala is located close to the hippocampus, in the frontal portion of the temporal lobe.

Amygdala is the integrative centre for emotions, emotional behaviour, and motivation. 

Amygdalae are essential to the ability to feel certain emotions and to perceive them in other people. 

This is because it’s often considered the home of negative emotions and responses, such as the ‘fight or flight’ response and general anxiety. 

Using technologies that Professor Wang’s lab had previously used to track the paths of activated neurons in mice, the team found the CeAga was connected to many different areas of the brain – a finding she described as ‘a surprise’.         

General anaesthesia activates a specific subset of inhibitory neurons in the central amygdala, which they have called the CeAga neurons. 

Mice have a relatively larger central amygdala than humans, but Prof Wang said she had no reason to think that man has any different system for controlling pain.  

By giving mice a mild pain stimulus, the researchers could map all of the mice’s pain-activated brain regions.

At least 16 brain centres known to process the sensory or emotional aspects of pain were receiving inhibitory input from the CeAga, they found.    

Using a technology called optogenetics, which uses light to activate a small population of cells in the brain, the researchers found that by activating the CeAga neurons, they could turn off the ‘self-caring’ behaviours that a mouse exhibits when it suffers discomfort.

Both optogenetics and a general anesthetic activate the process.

‘We initially identified the switch by studying general anesthetics, so general anesthetics activate these switch neurons to turn off pain,’ said Professor Wang. 

Researchers found they could turn off behaviours a mouse exhibits when it feels uncomfortable, such as scratching, during bouts of pain

Researchers found they could turn off behaviours a mouse exhibits when it feels uncomfortable, such as scratching, during bouts of pain

Paw-licking or face-wiping behaviours – taken as symptoms of pain – were ‘completely abolished’ the moment the light was switched on to activate the anti-pain centre. 

‘It’s so drastic – they just instantaneously stop licking and rubbing,’ said Professor Wang. 

They also found that low-dose ketamine, an anaesthetic drug that allows sensation but blocks pain, activated the CeAga centre and wouldn’t work without it.

Now the researchers are going to look for drugs that can activate only those cells to suppress pain as potential future pain killers.

‘The other thing we’re trying to do is to sequence the hell out of these cells.’

The researchers are hoping to find the gene for a rare cell surface receptors – receptors embedded in the plasma membrane of cells used in signalling – that would enable a specific drug to activate CeAga and relieve pain.

The new study, published in Nature Neuroscience, follows up on earlier research in Professor Wang’s lab that looked at neurons that are activated, rather than suppressed, by general anaesthetics.

In a 2019 study, the team found that general anaesthesia promotes slow-wave sleep by activating the supraoptic nucleus of the brain. 

WHAT IS A NEURON AND HOW DOES IT WORK?

A neuron, also known as nerve cell, is an electrically excitable cell that takes up, processes and transmits information through electrical and chemical signals. It is one of the basic elements of the nervous system.

In order that a human being can react to his environment, neurons transport stimuli.

The stimulation, for example the burning of the finger at a candle flame, is transported by the ascending neurons to the central nervous system and in return, the descending neurons stimulate the arm in order to remove the finger from the candle. 

A typical neuron is divided into three parts: the cell body, the dendrites and the axon. The cell body, the centre of the neuron, extends its processes called the axon and the dendrites to other cells.Dendrites typically branch profusely, getting thinner with each branching. The axon is thin but can reach enormous distances. 

To make a comparable scale, the diameter of a neuron is about the tenth size of the diameter of a human hair. 

All neurons are electrically excitable. The electrical impulse mostly arrives on the dendrites, gets processed into the cell body to then move along the axon.

On its all length an axon functions merely as an electric cable, simply transmitting the signal. 

Once the electrical reaches the end of the axon, at the synapses, things get a little more complex. 

The key to neural function is the synaptic signalling process, which is partly electrical and partly chemical. 

Once the electrical signal reaches the synapse, a special molecule called neurotransmitter is released by the neuron.

This neurotransmitter will then stimulate the second neuron, triggering a new wave of electrical impulse, repeating the mechanism described above.



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Scientists claim to have found a small area of the brain in mice that can turn off their sense of pain like a light switch. 

US researchers say the amygdala, a small almond-shaped cluster of neurons located in each side of the brain, can turn off multiple parts of the brain that process pain.  

Beams of light activate a set of neurons in the amygdala, called ‘CeAga’ neurons, which inhibit ‘pain-promotion centres’ in the brain, they say.

In experiments, activating the CeAga neurons dramatically reduced signs of discomfort in mice who had received a mild pain stimulus.

While mice have a relatively large central amygdala compared to humans, it’s likely humans have a similar system for controlling pain.

The discovery could result in the creation of a new wave of pain-relieving drugs for humans. 

Neuron cells in the central amygdala of a mouse brain. Red, magenta and yellow cells (but not green or blue) are parts of a collection of neurons called the CeAga that has potent pain-suppression abilities

‘Pain is a complicated brain response,’ said study author Professor Fan Wang of Duke University in Durham, North Carolina, the US. 

‘It involves sensory discrimination, emotion, and autonomic – involuntary nervous system – responses. 

‘Treating pain by dampening all of these brain processes in many areas is very difficult to achieve. 

‘But activating a key node that naturally sends inhibitory signals to these pain-processing regions would be more robust.’ 

Professor Wang said most of the previous studies have focused on which regions are turned on by pain. 

‘People do believe there is a central place to relieve pain, that’s why placebos work,’ she said. 

‘The question is where in the brain is the centre that can turn off pain.  

The amygdala, shown here in red, is is the centre for emotions, emotional behaviour, and motivation. Humans have two amygdala - one in each temporal lobe of the brain

The amygdala, shown here in red, is is the centre for emotions, emotional behaviour, and motivation. Humans have two amygdala – one in each temporal lobe of the brain

‘But there are so many regions processing pain, you’d have to turn them all off to stop pain. Whereas this one centre can turn off the pain by itself.’

The amygdala is located in an area where few people would have thought to look for an anti-pain centre, the research team claim. 

WHAT IS THE AMYGDALA? 

The amygdala is an almond-shaped structure in the brain.

Humans have two amygdala – one in each temporal lobe of the brain.

Amygdalae are each formed of a cluster of nuclei – a collection of neurons, or nerve cells. 

Each amygdala is located close to the hippocampus, in the frontal portion of the temporal lobe.

Amygdala is the integrative centre for emotions, emotional behaviour, and motivation. 

Amygdalae are essential to the ability to feel certain emotions and to perceive them in other people. 

This is because it’s often considered the home of negative emotions and responses, such as the ‘fight or flight’ response and general anxiety. 

Using technologies that Professor Wang’s lab had previously used to track the paths of activated neurons in mice, the team found the CeAga was connected to many different areas of the brain – a finding she described as ‘a surprise’.         

General anaesthesia activates a specific subset of inhibitory neurons in the central amygdala, which they have called the CeAga neurons. 

Mice have a relatively larger central amygdala than humans, but Prof Wang said she had no reason to think that man has any different system for controlling pain.  

By giving mice a mild pain stimulus, the researchers could map all of the mice’s pain-activated brain regions.

At least 16 brain centres known to process the sensory or emotional aspects of pain were receiving inhibitory input from the CeAga, they found.    

Using a technology called optogenetics, which uses light to activate a small population of cells in the brain, the researchers found that by activating the CeAga neurons, they could turn off the ‘self-caring’ behaviours that a mouse exhibits when it suffers discomfort.

Both optogenetics and a general anesthetic activate the process.

‘We initially identified the switch by studying general anesthetics, so general anesthetics activate these switch neurons to turn off pain,’ said Professor Wang. 

Researchers found they could turn off behaviours a mouse exhibits when it feels uncomfortable, such as scratching, during bouts of pain

Researchers found they could turn off behaviours a mouse exhibits when it feels uncomfortable, such as scratching, during bouts of pain

Paw-licking or face-wiping behaviours – taken as symptoms of pain – were ‘completely abolished’ the moment the light was switched on to activate the anti-pain centre. 

‘It’s so drastic – they just instantaneously stop licking and rubbing,’ said Professor Wang. 

They also found that low-dose ketamine, an anaesthetic drug that allows sensation but blocks pain, activated the CeAga centre and wouldn’t work without it.

Now the researchers are going to look for drugs that can activate only those cells to suppress pain as potential future pain killers.

‘The other thing we’re trying to do is to sequence the hell out of these cells.’

The researchers are hoping to find the gene for a rare cell surface receptors – receptors embedded in the plasma membrane of cells used in signalling – that would enable a specific drug to activate CeAga and relieve pain.

The new study, published in Nature Neuroscience, follows up on earlier research in Professor Wang’s lab that looked at neurons that are activated, rather than suppressed, by general anaesthetics.

In a 2019 study, the team found that general anaesthesia promotes slow-wave sleep by activating the supraoptic nucleus of the brain. 

WHAT IS A NEURON AND HOW DOES IT WORK?

A neuron, also known as nerve cell, is an electrically excitable cell that takes up, processes and transmits information through electrical and chemical signals. It is one of the basic elements of the nervous system.

In order that a human being can react to his environment, neurons transport stimuli.

The stimulation, for example the burning of the finger at a candle flame, is transported by the ascending neurons to the central nervous system and in return, the descending neurons stimulate the arm in order to remove the finger from the candle. 

A typical neuron is divided into three parts: the cell body, the dendrites and the axon. The cell body, the centre of the neuron, extends its processes called the axon and the dendrites to other cells.Dendrites typically branch profusely, getting thinner with each branching. The axon is thin but can reach enormous distances. 

To make a comparable scale, the diameter of a neuron is about the tenth size of the diameter of a human hair. 

All neurons are electrically excitable. The electrical impulse mostly arrives on the dendrites, gets processed into the cell body to then move along the axon.

On its all length an axon functions merely as an electric cable, simply transmitting the signal. 

Once the electrical reaches the end of the axon, at the synapses, things get a little more complex. 

The key to neural function is the synaptic signalling process, which is partly electrical and partly chemical. 

Once the electrical signal reaches the synapse, a special molecule called neurotransmitter is released by the neuron.

This neurotransmitter will then stimulate the second neuron, triggering a new wave of electrical impulse, repeating the mechanism described above.



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