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 knocked on the door and asked me out the corridor.
“Your father’s very sick,” my mother said. “Your is dead.” And then I felt it. A crushing in my chest. I can still feel a glimpse of whenever I think of my father.
He was a doctor, a scientist, a paratrooper. He was a young, strong, happy, 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 you 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 we make mental pain better? Together with many scientists and physicians, I spent years 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 lab at Columbia University. Eric, won the Nobel Prize for his work on the basis of memory, was the ultimate mentor. Passionate, energetic and inspiring.
Under 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 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 did that, didn’t really realize that work on that receptor, which 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 step along that way was the work of Jaak Panksepp, my other great scientific mentor. In classical experiment, Panksepp separated puppies from their mothers for 15 minutes. Never more than that because he loved animals. When lose their mothers, they make a sound which is called the separation distress cry. And it goes like this.
(Imitates wailing)
Puppies do it, kittens do it, babies do it. All young mammals do it when they’re in pain or they miss their mothers. And we all know how this cry makes us feel inside.
Panksepp and his colleagues then traced the brain circuits that produce these cries in guinea pigs, and made a startling discovery. That these are the very same circuits that are active when feel sad and when they experience depression. And these circuits are part of the brain’s pain matrix that mediates our sensations of physical and mental pain.
But are we born with this terrible gift hardwired into our brains? Well, probably because like pain, mental pain is an alarm system. Its task is to damage. When babies lose their mothers, they hurt and cry. Which brings their mothers back, and it also makes them their mothers. In the wild, this is life-saving. Puppies and babies cannot survive without mothers.
So now we know why we have mental pain. It is the glue keeps us together in couples, in families and communities. And when someone we goes away or is taken away from us, it’s this pain which draws us back together. And once we realize this, then can answer an age-old question that poets and philosophers 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 the high price, the very high price, that we pay our ability to love. And personally, and, you know, I’ve been 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 endorphins or opioids, our very own feel-good molecules, the natural remedy both physical and mental pain. Endorphins are released in brain during aerobic exercise or when we’re close to someone we love, and immediately severe injuries.
And we now know what endorphins do, they attach to receptors in the brain, and the most important among are mu opioid receptors. And just like the receptor I worked on Kandel’s lab, mu opioid receptors are GPCR.
Here’s how they work. Like all GPCRs, mu receptors are made of seven spirals or loops that are together, sticking through both sides of the cell membrane. Like this, OK.
And when attach to mu opioid receptors from the outside, they cause them to change their shape. Like this, OK? this triggers a series 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 suffering severe physical or mental pain, you actually cause her brain to release endorphins. They to mu opioid receptors in her synapses and turn them on, and they soothe her pain.
And yet, sometimes mental 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. Narcotics work mainly by activating mu receptors.
footnote
But if so, can narcotics also treat the pain separation? It was Jaak Panksepp who found the answer. gave his puppies in a separation experiment tiny, tiny doses of morphine, lower than lowest doses that are used to treat physical pain, and puppies immediately stopped crying and started playing with each other as if they no longer miss their mothers.
Let’s go to humans now. When mental pain in humans becomes too intense to bear people, some people, will do anything stop it, even try to kill themselves. Indeed, and I’m saying this a clinical psychiatrist, unbearable 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 become less suicidal? A few years ago, together with Panksepp and other colleagues, my research team conducted a 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 are too low treat physical pain, helped many of them become less suicidal. But narcotics are extremely drugs. They may cause addiction, and they’re lethal in 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 receptors in different ways.
Now, if could find drugs that activate mu opioid receptors in a way resembles how endorphins activate them, we might be 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 remembered what I had learned in Kandel’s many, many years 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 when they’re activated by just one drug. our research team then used molecular computing technologies to create a virtual model of the human mu opioid receptor. And then, with the help of programs known molecular docking algorithms, we screened thousands of existing drugs on a virtual model of the receptor.
Eventually, found a way to teach an old dog, that’s the human mu opioid receptor, new tricks. We found two drugs that are not narcotics, and they work together in very, very small doses to activate the human mu opioid receptor.
I’m not telling you their names, because still have to run many tests and clinical trials before we can be certain that 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 line. Let’s summarize what we’ve seen. First and foremost, mental is real. It’s hardwired into our brains. And mental pain an essential 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, and work mainly, not exclusively, but mainly by activating mu opioid receptors.
Now, narcotics also activate mu opioid receptors, but in way that causes addiction and can lead to death. And this is why narcotics are so dangerous. New technologies have helped us identify two existing drugs that together may treat physical and pain without some of the severe side effects of narcotics. However, this is still a work in progress. It would be a few before it may become an approved treatment.
But, and this is last thing I’m going to say, regardless of drugs, you have the ability to help family and friends who are in severe physical 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 are used to treat physical pain. And his puppies immediately stopped crying and started playing with each as 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 huge factor for suicide.”
For more information about why mental pain is a significant risk for suicide, see here.
note
“A few years ago, together with Panksepp and other colleagues, research team conducted a 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 of buprenorphine, which are too low to treat physical pain, help many of them become less suicidal.”
For more about these study results, see here.
note
“Some GPCRs 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 one drug.”
For more information about how GPCRs may be activated by two drugs at the same time, see here.