I’m Yoram Youvel. I’m a psychiatrist and neuroscientist at the University of Jerusalem. And when I was 14 years old, my father died. I was sitting class when my mother and my grandfather knocked on the door and asked out to the corridor.
“Your father’s very sick,” my mother said. “Your father dead.” And then I felt it. A crushing pain in my chest. I can still a glimpse of it whenever I think of my father.
He was a doctor, scientist, a paratrooper. He was a young, strong, happy, man. He was my hero. And his death broke my heart.
Do remember the pain you felt when someone broke your heart? When your best friend or mother died? Or the man you loved told you that doesn’t love you anymore. You probably do.
But why do feel mental pain at all? And what’s the relationship between physical mental pain? And most importantly, how can we make mental better? Together with many scientists and physicians, I spent years for answers to these questions.
Now, growing up, I never the words, “We want you to be a doctor and a brain scientist your father.” But somehow that’s what happened. Twelve years after 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 the molecular basis of memory, was the ultimate mentor. Passionate, energetic and inspiring.
Under his guidance, studied a receptor. It’s a protein that’s part of a synapse. And synapses are structures through which nerve cells communicate each other. Now that receptor was a GPCR. That’s a G protein coupled receptor. I’ll explain what this means 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 that receptor, which seemed completely unrelated to my future work as a clinical psychiatrist, would day help us in our search for better treatments for physical and mental pain.
Now a big step along that way the work of Jaak Panksepp, my other great scientific mentor. In a classical experiment, 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 separation distress cry. And it goes like this.
(Imitates puppy wailing)
Puppies do it, kittens do it, babies do it. All young mammals do when they’re in pain or when they miss their mothers. And we all know how this makes us feel inside.
Panksepp and his colleagues then traced the brain circuits that these cries in guinea pigs, and they made a startling discovery. That these are the very circuits that are active when humans feel sad and when they depression. And these circuits are also part of the brain’s pain matrix that mediates our of physical and mental pain.
But why are we born this terrible gift hardwired into our brains? Well, probably because like any pain, mental pain is alarm system. Its task is to prevent damage. When lose their mothers, they hurt and they cry. Which brings mothers back, and it also makes them seek their mothers. In the wild, this is life-saving. 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 and communities. And when someone we love goes away or taken away from us, it’s this pain which draws us back together. And we realize this, then we can answer an age-old question that poets philosophers have been asking for thousands of years.
Does always hurt? What do you think? Does love always hurt? Yes, always hurts, of course. Because that’s what it’s supposed do. Mental pain is simply the high price, the very high price, that we pay for our ability love. And personally, and, you know, I’ve been around the block a couple 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 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 opioid receptors. And just like the receptor I worked on in Kandel’s lab, mu opioid receptors are GPCR.
Here’s how they work. all GPCRs, mu opioid receptors are made of seven or loops that are stacked together, sticking through both sides of the cell membrane. Like this, OK.
And when endorphins attach mu opioid receptors from the outside, they cause them to change their shape. this, OK? And this triggers a series of events the neurons which eventually ease the pain.
Now, forget the molecules a second. When you hug someone you love who is suffering from physical or mental pain, you actually cause her brain to release endorphins. They attach mu opioid receptors in her synapses and turn them on, and they soothe 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. work mainly by activating mu opioid receptors.
footnote
But if so, can also treat the pain of separation? It was Jaak who found the answer. Panksepp gave his puppies in a separation experiment tiny, doses of morphine, lower than the lowest doses that are used to treat physical pain, his puppies immediately stopped crying and started playing with each other as if they longer miss their mothers.
Let’s go to humans now. When mental pain in 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 risk factor for suicide.
footnote
But if narcotics treat physical pain, and if they can soothe the mental 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, buprenorphine, for four weeks.
We discovered that tiny, tiny doses of buprenorphine, which too low to treat physical pain, helped many of them become 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 to cause addiction. So narcotics and endorphins probably activate mu opioid receptors different ways.
Now, if we could find drugs that mu opioid receptors in a way that resembles how endorphins activate them, we might be able to 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.
footnote
Some GPCRs can activated by two different drugs at the same time. when this happens, the result may be different from what when they’re activated by just one drug. So our research team then used molecular computing technologies create a detailed virtual model of the human mu opioid receptor. And then, with the help of programs known as molecular docking algorithms, 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 receptor, some new tricks. We found two drugs that are not narcotics, and they work together in very, very doses to activate the human 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 what we think it does. But both of these have been around for many, many years, and they’ve used by millions of people. So we know that they’re 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. 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 that causes addiction and can lead to death. And this is why narcotics so dangerous. New computational technologies have helped us identify two drugs that together may treat physical and mental pain some of the severe side effects of narcotics. However, this still a work in progress. It would be a few years before it may become an approved treatment.
But, and is the last thing I’m going to say, regardless of drugs, you have the ability to help family and friends who are in physical or mental pain.
Thank you very much.
(Applause)
Footnotes
note
“Panksepp gave puppies, in a separation experiment, tiny, tiny doses of morphine – lower than lowest doses that are used to treat physical pain. his puppies immediately stopped crying and started playing with each as if they no longer miss their mothers.”
According to results from this 1978 study, morphine-treated puppies were quite alert moved about normally while isolated from their mothers.
note
“Unbearable mental pain is a huge risk factor for suicide.”
For more information about mental pain is a significant risk factor for suicide, here.
note
“A few years ago, together with Panksepp other colleagues, my research team conducted a clinical trial. We gave who were severely suicidal, very low doses of a narcotic drug, buprenorphine car buprenorphine for four weeks. We discovered that tiny, tiny doses buprenorphine, which are too low to treat physical pain, help many of them become less suicidal.”
For information about these study results, see here.
note
“Some GPCRs can be activated by different drugs at the same time. And when this happens, the result may be different for what happens when they’re activated by just one drug.”
For more information about how GPCRs be activated by two different drugs at the same time, see here.