I’m Yoram Youvel. I’m a psychiatrist and at the Hebrew University of 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 asked me out to corridor.
“Your father’s very sick,” my mother said. “Your father is dead.” And then I felt it. A crushing pain in 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 young, strong, happy, healthy man. He was my hero. And death broke my heart.
Do you remember the pain you felt when someone your heart? When your best friend or your mother died? Or the man loved told you that he doesn’t love you anymore. You 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 many scientists and physicians, I spent years searching for 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 died, I was a graduate student at Dr. Eric Kandel’s lab at University. Eric, who won the Nobel Prize for his on the molecular basis of memory, was the ultimate mentor. Passionate, energetic and inspiring.
Under his guidance, I studied a receptor. It’s a that’s part of 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 what 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 my future work as a clinical psychiatrist, would one day help us in our search for better treatments for and mental pain.
Now a big step along that way was the work of Jaak Panksepp, my other great 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 a sound which is called the separation distress cry. And it goes like this.
(Imitates puppy wailing)
Puppies do it, kittens 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 cry makes us feel inside.
Panksepp and his colleagues then traced the circuits that produce these cries in guinea pigs, and they made a 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 alarm system. Its task is to damage. When babies lose their mothers, they hurt and they cry. Which their mothers back, and it also 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 mental pain. It is the that keeps us together in couples, in families and communities. And when someone we love goes away or is taken from us, it’s this pain which draws us back together. And once we this, then we can answer an age-old question that poets and philosophers been asking for thousands of years.
Does love always hurt? What you think? Does love always hurt? Yes, love always hurts, course. Because that’s what it’s supposed to do. Mental pain is simply the price, the very high price, that we pay for ability to love. And personally, and, you know, I’ve around the block a couple of times, personally, I it’s worth it.
But we’re not entirely defenseless against pain because our brains produce endorphins endogenous opioids, our very own feel-good molecules, the natural remedy for both physical and mental pain. Endorphins are in the brain during aerobic exercise or when we’re close to someone we love, and immediately after injuries.
And we now know what endorphins do, they attach to special in the brain, and the most important among them are mu opioid receptors. And like the receptor I worked on in Kandel’s lab, mu opioid receptors GPCR.
Here’s how they work. Like all GPCRs, mu opioid receptors are made of seven spirals or loops are stacked together, sticking through both sides of the membrane. Like 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 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 from severe physical or mental pain, you actually cause brain to release endorphins. They attach to mu opioid receptors in her synapses turn them on, and they soothe her pain.
And yet, sometimes mental pain so intense that no amount of love can soothe it. But medicine powerful drugs that can ease any physical pain. These the narcotics or opioids like morphine. Narcotics work mainly by activating mu opioid receptors.
footnote
But if so, can narcotics also treat pain of separation? It was Jaak Panksepp who found the answer. Panksepp gave his puppies in a experiment tiny, tiny doses of morphine, lower than the lowest doses that are used to treat physical pain, and his puppies stopped crying and started playing with each other as they no longer miss their mothers.
Let’s go to humans now. When mental pain in humans becomes too intense to bear people, 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 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, together Panksepp and other colleagues, my research team conducted a clinical trial. We people who were severely suicidal very low doses of a narcotic drug, called buprenorphine, for four weeks.
We discovered tiny, tiny doses of buprenorphine, which are too low to treat physical pain, helped many them become less suicidal. But narcotics are extremely dangerous drugs. They may cause addiction, and they’re lethal in overdose. contrast, endorphins are not lethal in overdose, and they’re much likely to cause addiction. So narcotics and endorphins probably activate mu opioid receptors different ways.
Now, if we could find drugs that activate mu receptors in a way that resembles how endorphins activate them, we might be able to treat physical and mental pain some of the dangerous side effects of narcotics. And when research team came to this conclusion, I suddenly remembered what I had in Kandel’s lab many, many years ago.
footnote
Some GPCRs can be activated by two different at the same time. And when this happens, the result may 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 the human mu opioid receptor. And then, with the help of programs known as docking algorithms, we screened thousands of existing drugs on 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. 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 clinical trials before can be certain that their combination does exactly what we think it does. But of these drugs have been around for many, many years, and they’ve been 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 real. It’s hardwired into our brains. And mental pain is an part of mourning and depression and sadness. And when it gets severe enough, it can actually make people suicidal. are brain’s natural remedy for physical and mental pain, they work mainly, not exclusively, but mainly by activating mu opioid receptors.
Now, also activate mu opioid receptors, but in a way that causes addiction can lead to death. And this is why narcotics are so dangerous. computational technologies have helped us identify two existing drugs that together may treat physical and mental without some of the severe side effects of narcotics. However, this is a work in progress. It would be a few years before it become an approved treatment.
But, and this is the last I’m going to say, regardless of drugs, you have the ability to help family and friends who are in severe physical or pain.
Thank you very much.
(Applause)
Footnotes
note
“Panksepp gave his puppies, in a separation experiment, tiny, tiny doses of morphine – lower than the lowest doses that 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.”
According to results from 1978 study, morphine-treated puppies were quite alert and moved about normally while isolated from their mothers.
note
“Unbearable mental pain is huge risk factor for suicide.”
For more information about why mental is a significant risk factor for suicide, see here.
note
“A few years ago, together with Panksepp and other colleagues, my research team conducted clinical trial. We gave people who were severely suicidal, very low doses of a narcotic drug, car buprenorphine for four weeks. We discovered that tiny, tiny doses of buprenorphine, which too low to treat physical pain, help many of them become suicidal.”
For more information about these study results, see here.
note
“Some GPCRs can be activated by two different drugs at 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 may be activated by two different drugs at the same time, here.