I’m Yoram Youvel. I’m a psychiatrist and neuroscientist at the University of Jerusalem. And when I was 14 years old, my father died. was sitting in class when my mother and my grandfather knocked the door and asked me out to the corridor.
“Your father’s very sick,” 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 my father.
He was a doctor, a scientist, a paratrooper. He was a young, strong, happy, healthy man. He was my hero. his death broke my heart.
Do you remember the pain felt when someone broke your heart? When your best friend or your mother died? Or man you loved told you that he doesn’t love anymore. You probably do.
But why do we feel mental pain at all? And what’s the relationship between and mental pain? And most importantly, how can we make mental pain better? Together with many scientists and physicians, I spent years searching answers to these questions.
Now, growing up, I never heard the words, “We want you to be a doctor a brain scientist like 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 Prize for his work on the molecular basis of memory, was 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 receptor was a GPCR. That’s a G protein coupled receptor. I’ll explain what this means in a and then you’ll understand what this stack of markers is doing here.
And when I did that, didn’t really realize that work on that receptor, which seemed completely to my future work as a clinical psychiatrist, would one day help us in our search 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 a classical 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 called the separation distress cry. And it goes like this.
(Imitates puppy wailing)
Puppies it, kittens do it, babies do it. All young mammals 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 circuits that produce these cries in guinea pigs, and made a startling discovery. That these are the very circuits that are active when humans feel sad and when they depression. And these circuits are also part of the brain’s pain that mediates our sensations of physical and mental pain.
But why are we born this terrible gift hardwired into our brains? Well, probably because any pain, mental pain is an alarm system. Its task is to 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 we know why we have mental pain. It is the glue that keeps us together in couples, families and communities. And when 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 have been asking for thousands of years.
Does love always hurt? What do you think? Does love hurt? Yes, love always hurts, of course. Because that’s what it’s supposed to do. Mental is simply the high price, the very high price, we pay for our ability to love. And personally, and, you know, I’ve been around the block a couple times, personally, I think it’s worth it.
But we’re entirely defenseless against pain because our brains produce endorphins or endogenous opioids, our very own feel-good molecules, the natural remedy for physical 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 do, they attach to special receptors in the brain, and the most important among them 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, opioid 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 them to change their shape. Like this, OK? And triggers 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 suffering from severe physical or mental pain, you actually cause brain to release endorphins. They attach to mu opioid receptors in her synapses and turn them on, and they soothe her pain.
And yet, sometimes mental pain gets so intense that no amount of love 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 opioid receptors.
footnote
But if so, narcotics also treat the pain of separation? It was Jaak Panksepp who found the answer. Panksepp gave his in a separation experiment tiny, tiny doses of morphine, lower than lowest doses that are used to treat physical pain, and his puppies immediately stopped crying and started playing with each other as if no longer miss their mothers.
Let’s go to humans now. When mental pain in humans becomes intense to bear people, some people, will do anything to it, even try to kill themselves. Indeed, and I’m saying this as a psychiatrist, unbearable mental pain is a huge risk factor for suicide.
footnote
But if narcotics treat physical pain, and if they can soothe mental pain of separation, can they also help suicidal people become less suicidal? A few ago, together with Panksepp and other colleagues, my research team conducted a trial. We gave people who were severely suicidal very low doses a narcotic drug, called buprenorphine, for four weeks.
We that tiny, tiny doses of buprenorphine, which are too low to treat physical pain, helped many of them become less suicidal. But narcotics are extremely dangerous drugs. They may cause addiction, they’re lethal in overdose. In contrast, endorphins are not lethal overdose, and they’re much less likely to cause addiction. So narcotics and endorphins probably activate mu opioid receptors in 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 physical and mental pain without some of the dangerous side effects of narcotics. And when my research team came this conclusion, I suddenly remembered what I had learned in Kandel’s lab many, many years ago.
footnote
GPCRs can be activated by two different drugs at the same time. when this happens, the result may be different from what when they’re activated by just one drug. So our team then used molecular computing technologies to create a detailed virtual model of the human mu receptor. And then, with the help of programs known as molecular 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 mu opioid receptor, some new tricks. We found two that 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 and clinical trials before we can be certain that their combination does exactly what think it does. But both of these drugs have been around for many, many years, and they’ve used 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 essential part of mourning depression and sadness. And when it gets severe enough, can actually make people suicidal. Endorphins are brain’s natural remedy for and mental pain, and 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. New computational technologies have helped us identify two existing drugs that may treat physical and mental pain without some of the severe side effects of narcotics. However, this 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 the ability to help family and 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, tiny doses of – lower than the lowest doses that are used to treat physical pain. And his puppies immediately 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 about normally while isolated from their mothers.
note
“Unbearable pain is a huge risk factor for suicide.”
For more information about why mental pain is a risk factor for suicide, see here.
note
“A few years ago, together with Panksepp other colleagues, my research team conducted a clinical trial. gave people who were severely suicidal, very low doses of narcotic drug, buprenorphine car buprenorphine for four weeks. We discovered that tiny, tiny doses buprenorphine, which are too low to treat physical pain, help many of them become less suicidal.”
For more information these study results, see here.
note
“Some GPCRs can be activated by two different drugs at the same time. And when this happens, the result may be different for what happens they’re activated by just one drug.”
For more information about how GPCRs may be activated by two different at the same time, see here.