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 sitting in class when my mother and my grandfather knocked on the and asked me out to the corridor.
“Your father’s very sick,” my mother said. “Your father is dead.” And then I it. A crushing pain in my chest. I can still feel a glimpse of it I think of my father.
He was a doctor, a scientist, 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 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 at all? And what’s the relationship between physical and mental pain? And most importantly, how can we make mental pain better? Together with scientists and physicians, I spent years searching for answers to 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 a graduate student at Dr. Eric Kandel’s lab at University. Eric, who won the Nobel Prize for his work on molecular basis of memory, was the ultimate mentor. Passionate, energetic inspiring.
Under his guidance, I studied a receptor. It’s a protein that’s part a synapse. And synapses are structures through which nerve cells communicate with other. Now that receptor was a GPCR. That’s a G protein coupled receptor. I’ll explain this means in a minute and then you’ll understand what this stack of markers is 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 for physical and mental pain.
Now a big step along that way was the work of Panksepp, my other great scientific mentor. In a classical experiment, Panksepp separated puppies their mothers for 15 minutes. Never more than that because he loved animals. puppies lose their mothers, they make a sound which is the separation distress cry. And it goes like this.
(Imitates wailing)
Puppies do it, kittens do it, babies do it. All mammals do it 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 produce these in guinea pigs, and they made a startling discovery. That these the very same circuits that are active when humans feel sad and when experience 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 with this terrible gift hardwired into our brains? Well, because like any pain, mental pain is an alarm system. Its task to prevent damage. When babies lose their mothers, they hurt and they cry. Which brings their back, and it also makes them seek their mothers. the wild, this is life-saving. Puppies and babies cannot without their mothers.
So now we know why we have mental pain. It is glue that keeps us together in couples, in families and communities. And someone we love goes away or is taken away from us, it’s this pain which us back together. And once we realize this, then we can answer an age-old question that poets and philosophers been asking for thousands of years.
Does love always hurt? What do you think? Does love always hurt? Yes, love always hurts, of course. that’s what it’s supposed to do. Mental pain is simply the high price, the very high price, that pay for our ability to love. And personally, and, you know, I’ve 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 or endogenous opioids, our very own feel-good molecules, the natural remedy for both physical and mental pain. Endorphins are released the brain during aerobic exercise or when we’re close to someone we love, immediately after severe injuries.
And we now know what endorphins do, they attach to special receptors in the brain, and the important among them are mu opioid receptors. And just like the 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 seven spirals or loops that are stacked together, sticking through both of the cell membrane. Like this, OK.
And when endorphins to mu opioid receptors from the outside, they cause them to change their shape. Like this, OK? And this triggers a series events inside the neurons which eventually ease the pain.
Now, forget molecules for a second. When you hug someone you love who is suffering from severe physical or mental pain, you cause her brain to release endorphins. They attach to mu opioid receptors in her synapses and turn on, and they soothe her pain.
And yet, sometimes mental pain gets so intense that no amount of love can soothe it. 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.
footnote
But so, can narcotics also treat the pain of separation? was Jaak Panksepp who found the answer. Panksepp gave his puppies in a separation experiment tiny, tiny doses of morphine, 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 no longer miss mothers.
Let’s go to humans now. When mental pain in humans becomes too intense bear people, some people, will do anything to stop it, even try to kill themselves. Indeed, and I’m saying as a clinical psychiatrist, unbearable mental pain is a huge factor for 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 few years ago, with Panksepp and other colleagues, my research team conducted a clinical trial. We gave people who were severely suicidal very low doses of narcotic drug, called buprenorphine, for four weeks.
We discovered that tiny, doses of buprenorphine, which are too low to treat physical pain, helped many of them become less suicidal. But narcotics are dangerous drugs. They may cause addiction, and they’re lethal in overdose. In contrast, endorphins are not in overdose, and they’re much less likely to cause addiction. So narcotics endorphins probably activate mu opioid receptors in different ways.
Now, if we could find drugs that activate mu opioid receptors a way that resembles how endorphins activate them, we might be able to treat physical mental pain without some of the dangerous side effects of narcotics. And when my research 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. And when this happens, the result may be different from what happens when they’re activated by just one drug. So our team then used molecular computing technologies to create a detailed 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 virtual model of the receptor.
Eventually, we found a way to an old dog, that’s the human mu opioid receptor, some new tricks. We two drugs that are not narcotics, and they work together very, very small doses to activate the human mu opioid receptor.
I’m not telling their names, because we still have to run many tests and clinical trials before we can be that their combination does exactly what we think it does. But both of these drugs have been around for many, years, and they’ve been used by millions of people. So we know that they’re safe humans.
Here’s our bottom line. Let’s summarize what we’ve seen. First and foremost, mental pain is real. It’s into our brains. And mental pain is an essential part of mourning and depression and sadness. And when it severe enough, it can actually make people suicidal. Endorphins are brain’s natural for physical and mental pain, and they work mainly, not exclusively, but by activating mu opioid receptors.
Now, narcotics also activate opioid receptors, but in a way that causes addiction and can lead death. And this is why narcotics are so dangerous. New computational technologies have helped us identify existing drugs that together may treat physical and mental pain without some of the severe side of narcotics. However, this is still a work in progress. It would be few years before it may become an approved treatment.
But, and this is the thing I’m going to say, regardless of drugs, you the ability to help family and friends who are in severe physical or mental pain.
Thank you much.
(Applause)
Footnotes
note
“Panksepp gave his puppies, in a experiment, tiny, tiny doses of morphine – lower than the doses that are used to treat physical pain. And his puppies immediately stopped crying and started playing with each other if they no longer miss their mothers.”
According to results this 1978 study, morphine-treated puppies were quite alert and moved normally while isolated from their mothers.
note
“Unbearable mental pain is a risk factor for suicide.”
For more information about why mental pain is a significant risk factor for suicide, here.
note
“A few years ago, together with Panksepp and colleagues, my research team conducted a clinical trial. We gave people who were severely suicidal, very doses of a narcotic drug, buprenorphine car buprenorphine for four weeks. discovered that tiny, tiny doses of buprenorphine, which are too low treat physical pain, help many of them become less suicidal.”
For more information about these study results, see here.
note
“Some can be activated by two different drugs at the same time. And when this happens, the result be different for what happens when they’re activated by just one drug.”
For more information about how may be activated by two different drugs at the same time, see here.