I’m Yoram Youvel. I’m a psychiatrist and neuroscientist at the Hebrew University Jerusalem. And when I was 14 years old, my father died. I was sitting in class when mother and my grandfather knocked on the door and me out to the corridor.
“Your father’s very sick,” my mother said. “Your father is dead.” And then I felt it. crushing pain in my chest. I can still feel a glimpse of it whenever I think of father.
He was a doctor, a scientist, a paratrooper. He 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 or your mother died? Or the man you loved told you that doesn’t love you anymore. You probably do.
But why we feel mental pain at all? And what’s the relationship physical and mental pain? And most importantly, how can we make mental pain better? with many scientists and physicians, I spent years searching answers to these questions.
Now, growing up, I never heard the words, “We want you to be a doctor and a 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 Nobel Prize for his work on the molecular basis memory, was the ultimate mentor. Passionate, energetic and inspiring.
Under his guidance, I studied receptor. It’s a protein that’s part of a synapse. And synapses are structures through 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 and then you’ll understand what this stack of markers is here.
And when I did that, I didn’t really realize that work that receptor, which seemed completely unrelated to my future as a clinical psychiatrist, would one day help us in our for better treatments for physical and mental pain.
Now a big step along that way was the work of Jaak Panksepp, other great scientific mentor. In a classical experiment, Panksepp separated puppies from mothers for 15 minutes. Never more than that because loved animals. When puppies lose their mothers, they make sound which is called the separation distress cry. And it goes like this.
(Imitates puppy wailing)
Puppies it, kittens do it, babies do it. All young mammals do it when they’re in pain or when they their mothers. And we all know how this cry makes us feel inside.
Panksepp his colleagues then traced the brain circuits that produce these cries in guinea pigs, and they a startling discovery. That these are the very same circuits that are 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 mental pain.
But why are we born with this terrible hardwired into our brains? Well, probably because like any pain, mental pain is an system. Its task is to prevent damage. When babies their mothers, they hurt and they cry. Which brings their mothers back, and it makes them seek their mothers. In the wild, this life-saving. Puppies and babies cannot survive without their mothers.
So now we know why we have pain. It is the glue that keeps us together in couples, in families and communities. And when someone we love goes 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 hurt? What do you think? Does love always hurt? Yes, love always hurts, of course. Because that’s what it’s to do. Mental pain is simply the high price, the high price, that we pay for our ability to love. And personally, and, you know, I’ve been around the a couple of times, personally, I think it’s worth it.
But we’re entirely defenseless against pain because our brains produce endorphins or endogenous opioids, our very own feel-good molecules, natural remedy for both physical and mental pain. Endorphins are released in the brain during aerobic exercise or when we’re close someone we love, and immediately after severe injuries.
And we now know what endorphins do, they attach special receptors in the brain, and the most important among them are mu opioid receptors. And just like the receptor I on in Kandel’s lab, mu opioid receptors are GPCR.
Here’s how they work. Like all GPCRs, mu opioid receptors are made of spirals or loops that are stacked together, sticking through both sides of the cell membrane. this, OK.
And when endorphins attach to mu opioid receptors from the outside, they cause them to their shape. Like this, OK? And this triggers a series of events the neurons which eventually ease the pain.
Now, forget the molecules for a second. When you hug someone you love who is suffering severe physical or mental pain, you actually cause her brain release endorphins. They attach to mu opioid receptors in her synapses and turn them on, and they soothe her pain.
And yet, sometimes mental gets so intense that no amount of love can soothe it. But medicine has powerful drugs can ease any physical pain. These are the narcotics or opioids like morphine. Narcotics work mainly activating mu opioid receptors.
footnote
But if so, can narcotics also treat the pain separation? It was Jaak Panksepp who found the answer. Panksepp gave his in a separation experiment tiny, tiny doses of morphine, lower than lowest doses that are used to treat physical pain, and his puppies immediately stopped crying started playing with each other as if they no miss their mothers.
Let’s go to humans now. When pain in humans becomes too intense to bear people, some people, will do anything to stop it, try to kill themselves. Indeed, and I’m saying this a clinical psychiatrist, unbearable mental pain is a huge risk factor suicide.
footnote
But if narcotics treat physical pain, and if they can the mental pain of separation, can they also help suicidal people become less suicidal? A years ago, together with Panksepp and other colleagues, my research team a clinical trial. We gave people who were severely suicidal very low doses of a narcotic drug, called buprenorphine, for 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 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 and endorphins probably activate mu opioid receptors in different ways.
Now, if we could find drugs that activate mu opioid receptors in a way resembles how endorphins activate them, we might be able to treat and mental pain without some of the dangerous side effects of narcotics. And when my research team came to conclusion, I suddenly remembered what I had learned in Kandel’s lab many, many years ago.
footnote
Some GPCRs can be activated by two drugs at the same time. And when this happens, the result may be different what happens when they’re activated by just one drug. So our research then used molecular computing technologies to create a detailed virtual model of the mu opioid receptor. And then, with the help of programs known as molecular algorithms, we screened thousands of existing drugs on a virtual model of the receptor.
Eventually, found a way to teach an old dog, that’s the human mu opioid receptor, new tricks. We found two drugs that are not narcotics, and they together in very, very small doses to activate the mu opioid receptor.
I’m not telling you their names, because we still have to run many tests and trials before we can be certain that their combination does exactly we think it does. But both of these drugs have been around for many, many years, and they’ve been used 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 foremost, mental pain is real. It’s hardwired into our brains. And mental pain is an essential part mourning and depression and sadness. And when it gets severe enough, can actually make people suicidal. Endorphins are brain’s natural remedy for physical and mental pain, and they work mainly, not exclusively, but by activating mu opioid receptors.
Now, narcotics also activate mu opioid receptors, but in way that causes addiction and can lead to death. And this is why are so dangerous. New computational technologies have helped us identify existing drugs that together may treat physical and mental pain some of the severe side effects of narcotics. However, this is still a work in progress. 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 to help family and friends who are in severe physical or mental pain.
Thank very much.
(Applause)
Footnotes
note
“Panksepp gave his puppies, in a separation experiment, tiny, tiny doses of morphine – than the lowest doses that are used to treat pain. And his puppies immediately stopped crying and started playing with each other as if no longer miss their mothers.”
According to results from this 1978 study, morphine-treated puppies were quite alert and moved about normally while isolated from their mothers.
note
“Unbearable mental pain is a huge risk factor for suicide.”
For information about why mental pain is a significant risk factor for suicide, see here.
note
“A years ago, together with Panksepp and other colleagues, my team conducted a clinical trial. We gave people who were severely suicidal, very low doses of a narcotic drug, buprenorphine car buprenorphine for weeks. We discovered that tiny, tiny doses of buprenorphine, which are too to treat physical pain, help many of them become less suicidal.”
For more information about these results, see here.
note
“Some GPCRs can be activated by two different drugs at the same time. And when this happens, result may be different for what happens when they’re activated just one drug.”
For more information about how GPCRs may be activated two different drugs at the same time, see here.