I’m Yoram Youvel. I’m a psychiatrist and neuroscientist at the Hebrew University Jerusalem. And when I was 14 years old, my father died. I was sitting in class when my mother and grandfather knocked on the door and asked me out to the corridor.
“Your father’s very sick,” my mother said. “Your father is dead.” And then felt it. A crushing pain in my chest. I can still feel a glimpse of it I think of my father.
He was a doctor, a scientist, a paratrooper. was a young, strong, happy, healthy man. He was my hero. And his death my heart.
Do you remember the pain you felt when someone broke your heart? When your best friend or your mother died? Or the man loved told you that he doesn’t love you anymore. You probably do.
But why we feel mental pain at all? And what’s the relationship between and mental pain? And most importantly, how can we make pain better? Together with many scientists and physicians, I years searching for answers to these questions.
Now, growing up, I never heard the words, “We you to be a doctor and a brain scientist like father.” But somehow that’s what happened. Twelve years after my father died, I was a graduate student at Dr. Kandel’s lab at Columbia University. Eric, who won the Prize for his work on the molecular basis 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 a synapse. And are structures through which nerve cells communicate with each other. that receptor was a GPCR. That’s a G protein coupled receptor. I’ll explain this means in a minute and then you’ll understand what stack of markers is doing here.
And when I did that, I didn’t really realize that work that receptor, which seemed completely unrelated to my future work as a clinical psychiatrist, would one day help us our search for better treatments for physical and mental pain.
Now a big step along that was the work of Jaak Panksepp, my other great scientific mentor. In a classical experiment, Panksepp separated puppies their mothers for 15 minutes. Never more than that because he loved animals. When puppies their mothers, they make a sound which is called separation distress cry. And it goes like this.
(Imitates puppy wailing)
Puppies do it, do it, babies do it. All young mammals do it when they’re in pain when they miss their mothers. And we all know how this cry makes us feel inside.
Panksepp and his colleagues then the brain circuits that produce these cries in guinea pigs, and they made a startling discovery. That these are the same circuits that are active when humans feel sad and when experience depression. And these circuits are also part of the brain’s pain matrix that mediates sensations of physical and mental pain.
But why are we born with this terrible gift hardwired into brains? Well, probably because like any pain, mental pain is an alarm system. Its task is prevent damage. When babies lose their mothers, they hurt and they cry. Which brings their mothers back, and it also makes 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. is the glue that keeps us together in couples, in and communities. And when someone we love goes away or taken away from us, it’s this pain which draws 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 always hurt? Yes, love always hurts, course. Because that’s what it’s supposed to do. Mental is simply the high price, the very high price, that we for our ability to love. And personally, and, you know, I’ve around the block a couple of times, personally, I think it’s it.
But we’re not entirely defenseless against pain because our brains produce or endogenous opioids, our very own feel-good molecules, the natural remedy for both physical and pain. Endorphins are released in the 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 special receptors in the brain, and most important among them are mu opioid receptors. And just the receptor I worked on in Kandel’s lab, mu opioid receptors 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 them to change shape. Like this, OK? And this triggers a series of events inside neurons which eventually ease the pain.
Now, forget the molecules for a second. When you someone you love who is suffering from severe physical or mental pain, actually cause her brain to release endorphins. They attach to mu opioid receptors in her synapses and them on, and they soothe her pain.
And yet, sometimes pain gets so intense that no amount of love can it. But medicine has powerful drugs that can ease any physical pain. These are the narcotics opioids like morphine. Narcotics work mainly by activating mu opioid receptors.
footnote
But if so, can narcotics also treat the pain of separation? It was Jaak Panksepp who found the answer. Panksepp gave puppies in a separation experiment tiny, tiny doses of morphine, lower than the lowest that are used to treat physical pain, and his puppies stopped crying and started playing with each other as if they no longer miss 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 as a clinical psychiatrist, unbearable mental is a huge risk factor for suicide.
footnote
if narcotics treat physical pain, and if they can soothe the mental pain separation, can they also help suicidal people become less suicidal? A few years ago, together with Panksepp and other colleagues, research 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 buprenorphine, which are too low to treat physical 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 cause addiction. So narcotics and endorphins activate mu opioid receptors in different ways.
Now, if we find drugs that activate mu opioid receptors in a that resembles how endorphins activate them, we might be able to treat physical and mental without some of the dangerous side effects of narcotics. And when my research team to this conclusion, I suddenly remembered what I had learned in Kandel’s lab many, many ago.
footnote
Some GPCRs can be activated by two different drugs at the same time. And when happens, the result may be different from what happens when they’re activated just one drug. So 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 as docking algorithms, we screened thousands of existing drugs on a virtual of the receptor.
Eventually, we found a way to teach an old dog, that’s the human mu opioid receptor, some tricks. We found two drugs that are not narcotics, and they work in very, very small doses to activate the human mu opioid receptor.
I’m not telling you their names, because we still have to many tests and clinical trials before we can be certain their combination does exactly what we think it does. But both of these drugs have been around for many, many years, and they’ve been used by millions of people. So we know they’re safe for humans.
Here’s our bottom line. Let’s what we’ve seen. First and foremost, mental pain is real. It’s hardwired into our brains. And mental pain is an essential of mourning and depression and sadness. And when it gets severe enough, can actually make people suicidal. Endorphins are brain’s natural remedy physical and mental pain, and they work mainly, not exclusively, but mainly by activating mu opioid receptors.
Now, narcotics also activate mu receptors, but in a way 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 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 it 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 and friends 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 morphine – lower than the lowest doses that are used to treat pain. And his puppies immediately stopped crying and started playing with each other if they no longer miss their mothers.”
According to results from this 1978 study, morphine-treated puppies were quite alert moved about normally while isolated from their mothers.
note
“Unbearable mental pain is a huge risk factor suicide.”
For more information about why mental pain is a risk factor for suicide, see here.
note
“A few years ago, together 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 car buprenorphine for four weeks. We discovered that tiny, doses 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 may be different for what happens when they’re activated just one drug.”
For more information about how GPCRs may be activated by two different at the same time, see here.