Why Broken Hearts Hurt — and What Heals Them | Yoram Yovell | TED

Summary

In this talk, Yoram Youvel, a psychiatrist and neuroscientist, explores the nature of mental pain, drawing on personal experience and scientific research. He discusses the brain's pain matrix, the role of endorphins in pain relief, and the potential of non-narcotic drugs to treat both physical and mental pain without the risks of addiction and overdose. Youvel emphasizes the importance of mental pain in human relationships and the ongoing quest for safer, more effective treatments.

Takeaways

• 😢 The speaker, Yoram Youvel, experienced profound mental pain after his father's death, which led him to explore the nature of mental pain.
• 🧠 Mental pain is closely linked to physical pain, sharing similar brain circuits that are part of the brain's pain matrix.
• 🐕 Jaak Panksepp's research with separated puppies revealed that the distress cries of young mammals are linked to human feelings of sadness and depression.
• 🧬 Yoram's work in Dr. Eric Kandel’s lab studying GPCRs laid the foundation for understanding receptors involved in pain and pleasure.
• 🤔 Mental pain serves as an alarm system, prompting us to seek social connections and avoid harm, thus playing a crucial role in our survival and relationships.
• ❤️ Love and mental pain are intertwined, as the capacity to love comes with the potential for heartache.
• 🏃‍♂️ Endorphins, the brain's natural 'feel-good' molecules, are released during exercise, social bonding, and in response to injury, helping to alleviate both physical and mental pain.
• 💊 Narcotics can reduce mental pain, as demonstrated by Panksepp's experiment with morphine on separated puppies, but they carry significant risks of addiction and overdose.
• 🔬 Yoram's team is developing new treatments for physical and mental pain by identifying drugs that activate mu opioid receptors in a safer manner than narcotics.
• 👨‍🔬 The use of molecular computing technologies and virtual models of the mu opioid receptor has led to the discovery of potential new treatments that could revolutionize pain management.

Q & A

What was the turning point in Yoram Youvel's life that led him to become a psychiatrist and neuroscientist?

The turning point in Yoram Youvel's life was the death of his father when he was 14 years old, which left him with a deep emotional pain and led him to pursue a career in understanding the brain and mental health.

What is a GPCR and how does it relate to Yoram Youvel's research?

A GPCR, or G protein-coupled receptor, is a protein that is part of a synapse and is involved in how nerve cells communicate with each other. Yoram Youvel's research involved studying a GPCR receptor in Dr. Eric Kandel’s lab, which later became relevant to his work on mental and physical pain.

What did Jaak Panksepp's experiment with separated puppies reveal about the brain's response to emotional pain?

Jaak Panksepp's experiment revealed that the separation distress cry in puppies was produced by the same brain circuits that are active in humans when they feel sad or experience depression. These circuits are also part of the brain's pain matrix, which mediates both physical and mental pain.

Why does mental pain exist according to the script?

Mental pain exists as an alarm system, similar to physical pain, to prevent damage. It serves as a glue that keeps individuals together in relationships and communities, and it prompts them to seek comfort and connection when they are in distress.

How do endorphins help in alleviating both physical and mental pain?

Endorphins, which are the brain's natural feel-good molecules, are released during activities like aerobic exercise, closeness to loved ones, and after severe injuries. They attach to mu opioid receptors in the brain, which helps to ease pain by triggering a series of events inside neurons.

What is the potential therapeutic use of buprenorphine as mentioned in the script?

In the script, a clinical trial found that very low doses of buprenorphine, a narcotic drug, helped reduce suicidal tendencies in severely suicidal individuals by soothing their mental pain.

How do narcotics differ from endorphins in their potential for addiction and overdose?

Narcotics, such as opioids, can cause addiction and are lethal in overdose, while endorphins are not lethal in overdose and are much less likely to cause addiction. This is due to the different ways they activate mu opioid receptors.

What is the significance of the discovery that some GPCRs can be activated by two different drugs simultaneously?

The discovery that some GPCRs can be activated by two different drugs at the same time suggests that the combination of drugs might produce different therapeutic effects than when they are used individually, potentially leading to safer treatments for pain.

What role did molecular computing technologies play in Yoram Youvel's research?

Molecular computing technologies were used to create a detailed virtual model of the human mu opioid receptor. This model, along with molecular docking algorithms, helped screen thousands of existing drugs to find potential combinations that could activate the receptor in a safer manner.

What is the current status of the research on finding safer alternatives to narcotics for treating pain?

The research is still a work in progress. While two existing drugs have been identified that may potentially treat physical and mental pain without severe side effects, they are yet to undergo further testing and clinical trials before they can become approved treatments.

Outlines

00:00

😢 The Impact of Loss and the Quest for Understanding Mental Pain

Yoram Youvel, a psychiatrist and neuroscientist, shares a deeply personal story about the death of his father at a young age and the intense emotional pain that followed. This experience sparked his interest in understanding the nature of mental pain and its relationship with physical pain. Youvel's journey led him to study under the guidance of Nobel laureate Dr. Eric Kandel, where he researched G protein-coupled receptors (GPCRs), which unexpectedly became relevant to his later work in treating mental pain. The narrative also touches on the work of Jaak Panksepp, who discovered that the brain circuits responsible for the distress cries of separated mammals are also involved in human sadness and depression, highlighting the evolutionary purpose of mental pain as an alarm system to prevent damage and maintain social bonds.

05:01

💊 The Role of Endorphins and Narcotics in Pain Relief

The speaker delves into the role of endorphins, the brain's natural 'feel-good' molecules, in alleviating both physical and mental pain. Endorphins are released during aerobic exercise, social bonding, and in response to severe injuries, and they act by binding to mu opioid receptors, which are a type of GPCR. The speaker explains how endorphins and narcotics like morphine work similarly to reduce pain by interacting with these receptors, but with significant differences in their potential for addiction and overdose. Panksepp's experiments with morphine on separated puppies demonstrate that even low doses of narcotics can alleviate mental distress. A clinical trial conducted by the speaker's team suggests that low doses of buprenorphine, a narcotic, can reduce suicidal tendencies in humans, but the risks associated with narcotics highlight the need for safer alternatives.

10:04

🧬 Innovative Drug Discovery for Safer Pain Management

The final paragraph outlines the speaker's team's innovative approach to finding safer alternatives to narcotics for treating pain. Using molecular computing technologies, they created a virtual model of the human mu opioid receptor and screened thousands of existing drugs to find non-narcotic combinations that could activate the receptor in a way similar to endorphins. The discovery of two drugs that have been safely used for many years and can work in tandem at low doses to activate the mu opioid receptor offers hope for a new treatment approach. While this research is ongoing and requires further testing and clinical trials, it represents a significant step towards developing safer pain management therapies. The speaker concludes by emphasizing the importance of support for those experiencing severe pain, regardless of the availability of medical treatments.

Keywords

💡Psychiatrist

A psychiatrist is a medical doctor who specializes in the diagnosis, treatment, and prevention of mental, emotional, and behavioral disorders. In the video, Yoram Youvel identifies himself as a psychiatrist, indicating his professional background in understanding and treating mental health issues. His personal experience with grief and his father's death likely influenced his career path and his interest in studying mental pain.

💡Neuroscientist

A neuroscientist is a scientist who studies the nervous system, including the brain and spinal cord, and how they affect behavior, learning, and cognition. Youvel's role as a neuroscientist is crucial as it relates to the video's exploration of the biological and neurological underpinnings of mental pain, linking it to the physical structure and function of the brain.

💡GPCR

GPCR stands for G protein-coupled receptor, which is a type of cell membrane receptor that, when activated, triggers a cascade of cellular responses. In the script, Youvel discusses his work on a GPCR receptor in Dr. Kandel's lab, which unexpectedly relates to his later work on mental pain. This term is central to understanding how certain drugs, like endorphins and narcotics, interact with the brain to modulate pain.

💡Endorphins

Endorphins are natural opioids produced by the body that function as neurotransmitters and are associated with feelings of pleasure and pain relief. The video explains that endorphins are released during activities like exercise and social bonding, and they play a key role in the brain's natural response to physical and mental pain. Youvel's research suggests that understanding endorphin function could lead to new treatments for pain.

💡Mu opioid receptors

Mu opioid receptors are a type of GPCR that respond to endorphins and are involved in the modulation of pain and reward. The video discusses how endorphins and narcotics interact with these receptors to alleviate pain, but with different consequences. Understanding the activation of mu opioid receptors is central to the development of safer pain treatments.

💡Mental pain

Mental pain refers to emotional suffering caused by psychological or social factors, such as grief, loss, or rejection. The video emphasizes that mental pain is a real and essential aspect of human experience, serving as an alarm system that can motivate social bonding and recovery. It is a central theme of the talk, as Youvel explores its biological basis and potential treatments.

💡Synapses

Synapses are the junctions through which neurons transmit signals to each other and are crucial for the brain's ability to process information. In the context of the video, Youvel's early research on a receptor involved in synapse function unexpectedly contributes to his later work on mental pain, highlighting the interconnectedness of neuroscience research.

💡Narcotics

Narcotics, such as morphine, are powerful drugs that are used to treat severe pain but can be addictive and potentially lethal. The video discusses how narcotics work by activating mu opioid receptors, similar to endorphins, but with a higher risk of negative side effects. This comparison is used to explore safer alternatives for pain management.

💡Separation distress cry

The separation distress cry is a vocalization made by young mammals, including humans, when they are in pain or separated from their caregivers. In the video, Youvel references an experiment by Jaak Panksepp, showing that the brain circuits responsible for this cry are also involved in human sadness and depression, linking early emotional responses to mental pain.

💡Clinical trial

A clinical trial is a research study that involves human participants and is designed to test the safety and effectiveness of medical interventions. The video mentions a clinical trial conducted by Youvel's team, which investigated the use of low doses of a narcotic drug to reduce suicidality in patients with severe mental pain, demonstrating the application of scientific research to real-world medical challenges.

💡Molecular docking algorithms

Molecular docking algorithms are computational methods used to predict how molecules, such as drugs, will interact with a target, like a receptor. In the video, Youvel's team uses these algorithms to screen existing drugs for their potential to activate mu opioid receptors in a way that might mimic endorphins, illustrating the intersection of computational technology and drug discovery.

Highlights

Yoram Youvel is a psychiatrist and neuroscientist at the Hebrew University of Jerusalem.

Youvel's interest in mental pain was deeply personal, triggered by the loss of his father at a young age.

He pursued his education under the guidance of Nobel laureate Dr. Eric Kandel at Columbia University.

Youvel studied GPCRs, which are crucial for understanding how nerve cells communicate.

Jaak Panksepp's work on separation distress in animals was foundational for understanding mental pain.

The brain circuits active during separation distress are also involved in human sadness and depression.

Mental pain serves as an alarm system, preventing damage and promoting social cohesion.

Endorphins, the brain's natural 'feel-good' molecules, can alleviate both physical and mental pain.

Mu opioid receptors are key targets for endorphins to reduce pain.

Narcotics like morphine can soothe mental pain, but they come with risks of addiction and overdose.

Youvel's team conducted a clinical trial using low doses of buprenorphine to reduce suicidality.

Computational technologies were used to model the human mu opioid receptor and screen potential drugs.

Two non-narcotic drugs were identified that may activate mu opioid receptors in a safer manner.

Mental pain is an essential part of the human experience, linked to mourning, depression, and sadness.

Narcotics activate mu opioid receptors but can lead to severe side effects.

The discovery of safer drug combinations could revolutionize the treatment of physical and mental pain.

Youvel emphasizes the importance of human connection in alleviating pain, regardless of medical advancements.

Transcripts

I'm Yoram Youvel.

I'm a psychiatrist and neuroscientist at the Hebrew University of Jerusalem.

And when I was 14 years old, my father died.

I was sitting in class

when my mother and my grandfather knocked on the door

and asked me out to the corridor.

"Your father's very sick," my mother said.

"Your father is dead."

And then I felt it.

A crushing pain in my chest.

I can still feel a glimpse of it whenever I think of my father.

He was a doctor, a scientist, a paratrooper.

He was a young, strong, happy, healthy man.

He was my hero.

And his death broke my heart.

Do you remember the pain you felt when someone broke your heart?

When your best friend or your mother died?

Or the man you loved told you that he doesn't love you anymore.

You probably do.

But why do we feel mental pain at all?

And what's the relationship between physical and mental pain?

And most importantly, how can we make mental pain better?

Together with many scientists and physicians,

I spent years searching for answers to these questions.

Now, growing up, I never heard the words,

"We want you to be a doctor and a brain scientist like your father."

But somehow that's what happened.

Twelve years after my father died,

I was a graduate student at Dr. Eric Kandel’s lab

at Columbia University.

Eric, who won the Nobel Prize

for his work on the molecular basis of memory,

was the ultimate mentor.

Passionate, energetic and inspiring.

Under his guidance, I studied a receptor.

It's a protein that's part of a synapse.

And synapses are structures through which nerve cells communicate with each other.

Now that receptor was a GPCR.

That's a G protein coupled receptor.

I'll explain what this means in a minute

and then you'll understand what this stack of markers is doing here.

And when I did that,

I didn't really realize that work on that receptor,

which seemed completely unrelated to my future work

as a clinical psychiatrist,

would one day help us in our search for better treatments

for physical and mental pain.

Now a big step along that way was the work of Jaak Panksepp,

my other great scientific mentor.

In a classical experiment,

Panksepp separated puppies from their mothers for 15 minutes.

Never more than that because he loved animals.

When puppies lose their mothers,

they make a sound which is called the separation distress cry.

And it goes like this.

(Imitates puppy wailing)

Puppies do it,

kittens do it, babies do it.

All young mammals do it

when they're in pain or when they miss their mothers.

And we all know how this cry makes us feel inside.

Panksepp and his colleagues then traced the brain circuits

that produce these cries in guinea pigs,

and they made a startling discovery.

That these are the very same circuits that are active when humans feel sad

and when they experience depression.

And these circuits are also part of the brain's pain matrix

that mediates our sensations of physical and mental pain.

But why are we born with this terrible gift

hardwired into our brains?

Well, probably because like any pain, mental pain is an alarm system.

Its task is to prevent damage.

When babies lose their mothers, they hurt and they cry.

Which brings their mothers back,

and it also makes them seek their mothers.

In the wild, this is life-saving.

Puppies and babies cannot survive without their mothers.

So now we know why we have mental pain.

It is the glue that keeps us together in couples, in families and communities.

And when someone we love goes away or is taken away from us,

it's this pain which draws us back together.

And once we realize this,

then we can answer an age-old question

that poets and philosophers have been asking for thousands of years.

Does love always hurt?

What do you think?

Does love always hurt?

Yes, love always hurts, of course.

Because that's what it's supposed to do.

Mental pain is simply the high price,

the very high price, that we pay for our ability to love.

And personally,

and, you know, I've been around the block a couple of times,

personally, I think it's worth it.

But we're not entirely defenseless against pain

because our brains produce endorphins

or endogenous opioids,

our very own feel-good molecules,

the natural remedy for both physical and mental pain.

Endorphins are released in the brain during aerobic exercise

or when we're close to someone we love,

and immediately after severe injuries.

And we now know what endorphins do,

they attach to special receptors in the brain,

and the most important among them are mu opioid receptors.

And just like the receptor I worked on in Kandel's lab,

mu opioid receptors are GPCR.

Here's how they work.

Like all GPCRs, mu opioid receptors are made of seven spirals

or loops that are stacked together,

sticking through both sides of the cell membrane.

Like this, OK.

And when endorphins attach to mu opioid receptors from the outside,

they cause them to change their shape.

Like this, OK?

And this triggers a series of events inside the neurons

which eventually ease the pain.

Now, forget the molecules for a second.

When you hug someone you love

who is suffering from severe physical or mental pain,

you actually cause her brain to release endorphins.

They attach to mu opioid receptors in her synapses and turn them on,

and they soothe her pain.

And yet, sometimes mental pain gets so intense

that no amount of love can soothe it.

But medicine has powerful drugs that can ease any physical pain.

These are the narcotics or opioids like morphine.

Narcotics work mainly by activating mu opioid receptors.

But if so, can narcotics also treat the pain of separation?

It was Jaak Panksepp who found the answer.

Panksepp gave his puppies in a separation experiment

tiny, tiny doses of morphine,

lower than the lowest doses that are used to treat physical pain,

and his puppies immediately stopped crying

and started playing with each other as if they no longer miss their mothers.

Let's go to humans now.

When mental pain in humans becomes too intense to bear

people, some people, will do anything to stop it,

even try to kill themselves.

Indeed, and I'm saying this as a clinical psychiatrist,

unbearable mental pain is a huge risk factor for suicide.

But if narcotics treat physical pain,

and if they can soothe the mental pain of separation,

can they also help suicidal people become less suicidal?

A few years ago,

together with Panksepp and other colleagues,

my research team conducted a clinical trial.

We gave people who were severely suicidal very low doses of a narcotic drug,

called buprenorphine, for four weeks.

We discovered that tiny, tiny doses of buprenorphine,

which are too low to treat physical pain,

helped many of them become less suicidal.

But narcotics are extremely dangerous drugs.

They may cause addiction, and they're lethal in overdose.

In contrast, endorphins are not lethal in overdose,

and they're much less likely to cause addiction.

So narcotics and endorphins probably activate mu opioid receptors

in different ways.

Now, if we could find drugs that activate mu opioid receptors

in a way that resembles how endorphins activate them,

we might be able to treat physical and mental pain

without some of the dangerous side effects of narcotics.

And when my research team came to this conclusion,

I suddenly remembered what I had learned in Kandel's lab many, many years ago.

Some GPCRs can be activated by two different drugs at the same time.

And when this happens,

the result may be different from what happens

when they're activated by just one drug.

So our research team then used molecular computing technologies

to create a detailed virtual model of the human mu opioid receptor.

And then, with the help of programs known as molecular docking algorithms,

we screened thousands of existing drugs on a virtual model of the receptor.

Eventually, we found a way to teach an old dog,

that's the human mu opioid receptor,

some new tricks.

We found two drugs that are not narcotics,

and they work together in very, very small doses

to activate the human mu opioid receptor.

I'm not telling you their names,

because we still have to run many tests and clinical trials

before we can be certain

that their combination does exactly what we think it does.

But both of these drugs have been around for many, many years,

and they've been used by millions of people.

So we know that they're safe for humans.

Here's our bottom line.

Let's summarize what we've seen.

First and foremost, mental pain is real.

It's hardwired into our brains.

And mental pain is an essential part of mourning and depression and sadness.

And when it gets severe enough, it can actually make people suicidal.

Endorphins are brain's natural remedy for physical and mental pain,

and they work mainly, not exclusively,

but mainly by activating mu opioid receptors.

Now, narcotics also activate mu opioid receptors,

but in a way that causes addiction and can lead to death.

And this is why narcotics are so dangerous.

New computational technologies have helped us identify two existing drugs

that together may treat physical and mental pain

without some of the severe side effects of narcotics.

However, this is still a work in progress.

It would be a few years before it may become an approved treatment.

But, and this is the last thing I'm going to say,

regardless of drugs,

you have the ability to help family and friends

who are in severe physical or mental pain.

Thank you very much.

(Applause)