I’m Yoram Youvel. I’m a psychiatrist and neuroscientist at Hebrew University of Jerusalem. And when I was 14 years old, my father died. I was sitting in class when my mother and my grandfather on the door and asked me out to the corridor.
“Your father’s sick,” my mother said. “Your father is dead.” And then I felt it. A crushing pain in my chest. can still feel a glimpse of it whenever I of my father.
He was a doctor, a scientist, a paratrooper. He a young, strong, happy, healthy man. He was my hero. 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 doesn’t love you anymore. You probably do.
But why we feel mental pain at all? And what’s the relationship between physical and pain? And most importantly, how can we make mental pain better? Together with many scientists and physicians, I spent searching for answers to these questions.
Now, growing up, I never heard the words, “We want to be a doctor and a brain scientist like your father.” But that’s what happened. Twelve years after my father died, I was a graduate student at Dr. Eric Kandel’s at Columbia 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, studied a receptor. It’s a protein that’s part of a synapse. And synapses are structures through which cells communicate with each other. Now that receptor was GPCR. That’s a G protein coupled receptor. I’ll explain what this means in a minute and you’ll understand what this stack of markers is doing here.
And I did that, I didn’t really realize that work on that receptor, which seemed completely unrelated to my future work as a psychiatrist, would one day help us in our search for better treatments physical and mental pain.
Now a big step along that way was the work of Jaak Panksepp, my other great scientific mentor. In a classical experiment, Panksepp separated puppies from 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 do it, babies do it. All mammals do it when they’re in pain or when they miss their mothers. And we all how this cry 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 are the very same circuits that are active when humans feel sad and when they experience depression. these circuits are also part of the brain’s pain matrix that mediates our of physical and mental pain.
But why are we with this terrible gift hardwired into our brains? Well, probably because like any pain, mental pain is an system. Its task is to prevent damage. When babies lose their mothers, they hurt and they cry. brings their 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 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 is taken away from us, it’s this pain which draws us together. And once we realize this, then we can answer an age-old question poets and philosophers have been asking for thousands of years.
Does love always hurt? What do you think? love always hurt? Yes, love always hurts, of course. Because that’s it’s supposed to do. Mental pain is simply the high price, the very high price, that we for our ability to love. And personally, and, you know, I’ve been around the block a couple of times, personally, I think it’s it.
But we’re not entirely defenseless against pain because our produce endorphins 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 in the brain, and the most important among them are mu opioid receptors. And just like receptor I worked on in Kandel’s lab, mu opioid receptors are GPCR.
Here’s how they work. Like all GPCRs, mu opioid receptors made of seven spirals or loops that are stacked together, through both sides of the cell membrane. Like this, OK.
And when endorphins attach to mu opioid receptors from the outside, they cause 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 a second. When you hug someone you love who is from severe physical or mental pain, you actually cause her brain 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 love can soothe it. But medicine has powerful drugs that ease any physical pain. These are the narcotics or opioids like morphine. Narcotics work by activating mu opioid receptors.
footnote
But if so, narcotics also treat the pain of separation? It was Jaak Panksepp who found the answer. Panksepp gave his puppies in separation experiment tiny, tiny doses of morphine, lower than the lowest doses that are used treat physical pain, and his puppies immediately stopped crying and started playing with each as if they no longer miss their mothers.
Let’s go to humans now. When pain in humans becomes too intense to bear people, some people, will do to stop it, even try to kill themselves. Indeed, 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 soothe the mental pain of separation, can they also help suicidal people less suicidal? A few years ago, together with Panksepp and other colleagues, my team conducted a clinical trial. We gave people who were severely suicidal very doses of a narcotic drug, called buprenorphine, for four 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 overdose. In contrast, endorphins are not lethal in overdose, and they’re much less likely to addiction. So narcotics and endorphins probably activate mu opioid in different ways.
Now, if we could find drugs that activate mu receptors in a way that resembles how endorphins activate them, we might be to treat physical and mental pain without some of the 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 activated by two different drugs at the same time. And this happens, the result may be different from what happens when they’re activated by just drug. So our research team then used molecular computing technologies to create a detailed virtual model of the human mu opioid receptor. And then, the help of programs known as molecular docking algorithms, we screened thousands of existing drugs on a model of the receptor.
Eventually, we found a way teach an old dog, that’s the human mu opioid receptor, some new tricks. We found two drugs are not narcotics, and they work together in very, very small doses to activate the human opioid receptor.
I’m not telling you their names, because we still have to run many tests and clinical before we can be certain that their combination does exactly what we think it does. But both of these drugs have been around for many, many years, they’ve been used by millions of people. So we know that they’re safe for humans.
Here’s our bottom line. Let’s summarize we’ve seen. First and foremost, mental pain is real. It’s hardwired our brains. And mental pain is an essential part of mourning and depression and sadness. And when it gets severe enough, it can 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 mu opioid receptors, but in a way that causes addiction and can lead to death. And this is why narcotics are so dangerous. New computational have helped us identify two 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. It would be a few years before may become an approved treatment.
But, and this is the last thing I’m going to say, regardless of drugs, you have the ability to help family friends who are in severe physical or mental pain.
Thank you very much.
(Applause)
Footnotes
note
“Panksepp gave his puppies, in a separation experiment, tiny, doses of morphine – lower than the lowest doses that are used 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 this 1978 study, morphine-treated puppies were quite alert and moved about normally while from their mothers.
note
“Unbearable mental pain is a huge risk factor for suicide.”
For more about why mental pain is a significant risk factor for suicide, here.
note
“A few years ago, together with and 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 of buprenorphine, which too low to treat physical pain, help many of them become less suicidal.”
For more information about study results, see here.
note
“Some GPCRs can be activated by two different drugs at the same time. when this happens, the result may be different for what when they’re activated by just one drug.”
For more information how GPCRs may be activated by two different drugs at the same time, see here.