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 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 felt it. crushing pain in my chest. I can still feel a glimpse it whenever I think of my father.
He was a doctor, a scientist, a paratrooper. He was a young, strong, happy, healthy man. was my hero. And his death broke my heart.
Do you remember the pain you felt when someone broke your heart? 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 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 heard 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 on the molecular 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 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 this stack of markers is doing here.
And when I that, I didn’t really realize that work on that receptor, which seemed unrelated to my future work as a clinical psychiatrist, would one day help us in our search for better treatments for physical and pain.
Now a big step along that way was the of Jaak Panksepp, my other great scientific mentor. In a experiment, Panksepp separated puppies from 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 puppy wailing)
Puppies do it, kittens do it, do it. All young mammals do it when they’re in pain or when they miss their mothers. And all know how this cry makes us feel inside.
Panksepp and his colleagues then traced the brain circuits produce these cries in guinea pigs, and they made a startling discovery. That these are very same circuits that are active when humans feel and when they experience depression. And these circuits are also part of brain’s pain matrix that mediates our sensations of physical and pain.
But why are we born with this terrible gift hardwired into our brains? Well, probably because like any pain, pain is an alarm system. Its task is to prevent damage. When babies lose their mothers, they and they cry. Which brings their mothers back, and it also makes them their mothers. In the wild, this is life-saving. Puppies 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 away or is 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 and have been asking for thousands of years.
Does love always hurt? What do you think? love always hurt? Yes, love always hurts, of course. that’s what it’s supposed to do. Mental pain is simply high price, the very high price, that we pay for ability to love. And personally, and, you know, I’ve been around the block a couple of times, personally, think it’s worth it.
But we’re not entirely defenseless pain because our brains produce endorphins or endogenous opioids, very own feel-good molecules, the natural remedy for both and mental pain. Endorphins are released in the brain during aerobic exercise when we’re close to someone we love, and immediately after severe injuries.
And we now know what endorphins do, they attach to special 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 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 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. Like this, OK? And this a series of events inside the neurons which eventually ease the pain.
Now, forget the molecules for second. When you hug someone you love who is suffering from severe physical or mental pain, you actually her brain to release endorphins. They attach to mu opioid receptors in her synapses and turn them on, and they her pain.
And yet, sometimes mental pain gets so intense no amount of love can soothe it. But medicine has powerful drugs that can ease physical pain. These are the narcotics or opioids like morphine. Narcotics work mainly by mu opioid receptors.
footnote
But if so, can narcotics also treat the of separation? It was Jaak Panksepp who found the answer. Panksepp his puppies in a separation experiment tiny, 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 no longer miss their mothers.
Let’s to humans now. When mental pain in humans becomes too intense to bear people, some people, will do to stop it, even try to kill themselves. Indeed, and I’m saying this as a clinical psychiatrist, mental pain is a huge risk factor for suicide.
footnote
But if narcotics treat physical pain, and if can soothe 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 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 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 lethal in overdose, and they’re much less likely to cause addiction. So narcotics and endorphins activate mu opioid receptors in different ways.
Now, if we could find drugs that activate mu opioid in a way that resembles how endorphins activate them, we might able to treat physical and mental pain without some of the dangerous effects of narcotics. And when my research team came to this conclusion, I suddenly what I had learned in Kandel’s lab many, many ago.
footnote
Some GPCRs can be activated by two different drugs the same time. And when this happens, the result may be different from what happens they’re activated by just one drug. So our research team then used molecular computing technologies to create detailed virtual model of the human mu opioid receptor. And then, with the help of known as molecular docking algorithms, we screened thousands of existing drugs on a virtual model of receptor.
Eventually, we found a way to teach an 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 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 what we think it does. But both of these drugs have been around for many, many years, and they’ve been used by of people. So we know that they’re safe for humans.
Here’s our bottom line. Let’s summarize what we’ve seen. and foremost, mental pain is real. It’s hardwired into our brains. And mental pain is essential part of mourning and depression and sadness. And when it gets severe enough, it can actually make suicidal. Endorphins are brain’s natural remedy for physical and mental pain, and 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 existing drugs together may treat physical and mental pain without some the severe side effects of narcotics. However, this is still a work progress. It would be a few years before it may become an approved treatment.
But, and this is the last thing I’m going 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 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 with each other as if they no longer miss their mothers.”
According to from this 1978 study, morphine-treated puppies were quite alert and moved about normally while isolated from mothers.
note
“Unbearable mental pain is a huge risk factor suicide.”
For more information about why mental pain is a significant risk factor for suicide, see here.
note
“A few ago, together with Panksepp and other colleagues, my research team a clinical trial. We gave people who were severely suicidal, very doses of a narcotic drug, buprenorphine car buprenorphine for four 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 study results, see here.
note
“Some GPCRs can be activated by two different drugs at same time. And when this happens, the result may different for what happens when they’re activated by just one drug.”
For more information about GPCRs may be activated by two different drugs at the same time, see here.