Understanding Mental Pain and Opioid Receptors

Mental pain is essential, but potentially treatable with non-narcotic drugs activating mu opioid receptors, offering hope for future treatments.

### Unveiling the Link Between Mental Pain and Endorphins: A New Hope for Pain Management
* 😢  Mental pain is an alarm system hardwired into our brains to prevent damage, and it plays a **crucial role in keeping us together** in couples, families, and communities.
* 💊  Endorphins, the brain's natural feel-good molecules, are released during aerobic exercise, when close to loved ones, and immediately after severe injuries, mainly working by **activating mu opioid receptors**.
* 💉  Narcotics like morphine also activate mu opioid receptors, and Jaak Panksepp's experiments showed that **tiny doses of morphine could soothe the mental pain of separation** in animals.
* 🩺  Severe mental pain is a significant risk factor for suicide, and a clinical trial led by Yoram Youvel's research team found that **very low doses of the narcotic drug buprenorphine helped severely suicidal individuals become less suicidal**.
* 🧪  By using molecular computing technologies and screening thousands of existing drugs, the research team identified two drugs that, when used together in very small doses, **activate the human mu opioid receptor**.
* 🩸 " 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**.
* 📆  While this discovery is still a work in progress and requires further tests and clinical trials, it holds promise for **treating physical and mental pain without the severe side effects of narcotics**.
* 🤝  Regardless of drugs, everyone has the ability to **help family and friends who are in severe physical or mental pain**.

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)

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

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The Journey of a Psychiatrist and Neuroscientist

Yoram Youvel, a psychiatrist and neuroscientist, shares his personal experience of losing his father and the emotional pain it caused.

His research, initially focused on a specific receptor in the brain, has led to a better understanding of physical and mental pain, as well as the development of improved treatments.

Through the work of his mentor, Jaak Panksepp, the brain circuits producing distress cries in mammals were discovered, further contributing to the study of pain.

The Purpose of Mental Pain and Its Connection to Love

Mental pain is hardwired into our brains as an alarm system to prevent damage, particularly in the case of babies needing their mothers for survival.

This type of pain serves as the glue that holds couples, families, and communities together, drawing loved ones back to each other.

The experience of love is inevitably linked to pain, as it is the price we pay for our ability to love, although our brains do produce endorphins as a natural remedy for both physical and mental pain.

The Role of Mu Opioid Receptors in Easing Pain and Distress

Mu opioid receptors, like other GPCRs, are made of seven stacked loops and are activated by endorphins to ease pain.

Narcotics such as morphine also activate these receptors, as demonstrated by Jaak Panksepp's experiment on puppies, showing they can soothe the pain of separation.

This leads to the question of whether narcotics can help reduce suicidal tendencies in people experiencing intense mental pain.

Using Low Doses of Buprenorphine to Treat Suicidal Tendencies

A clinical trial found that very low doses of the narcotic drug buprenorphine helped reduce suicidal tendencies.

The research team aims to find drugs that can activate the mu opioid receptor similarly to endorphins, potentially treating pain and mental health issues without the dangerous side effects of narcotics.

By using molecular computing technologies, the team discovered two non-narcotic drugs that, in combination, can activate the human mu opioid receptor in very small doses.

The Significance of Mental Pain and the Search for Safe Treatment

Mental pain is a real and hardwired part of human experience, often leading to severe outcomes like suicide.

Endorphins, which activate mu opioid receptors, offer a natural remedy for mental pain, in contrast to narcotics which can lead to addiction and death.

New computational technologies have identified potential drugs to treat physical and mental pain with fewer side effects, offering hope for the future.