I’m Youvel. I’m a psychiatrist and neuroscientist at the Hebrew University of Jerusalem. when I was 14 years old, my father died. was sitting in class when my mother and my knocked on the door and asked me out to the corridor.
“Your father’s very sick,” my mother said. “Your father dead.” And then I felt it. A crushing pain in my chest. I can feel a glimpse of it 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 remember the pain you felt when someone broke your heart? When your friend or your mother died? Or the man you loved 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 and mental pain? And most importantly, how can we make mental pain better? Together with scientists and physicians, I spent years searching for answers to these questions.
Now, growing up, I never heard the words, “We want you to be a doctor and a brain scientist like your father.” But somehow that’s happened. Twelve years after my father died, I was a graduate at Dr. Eric Kandel’s lab at Columbia University. Eric, who won the Prize for his work on the molecular basis of memory, the ultimate mentor. Passionate, energetic and inspiring.
Under his guidance, I a receptor. It’s a protein that’s part of a synapse. And synapses are structures through which nerve cells communicate with other. Now that receptor was a 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 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 help us in our search for better treatments for physical and mental pain.
Now a big along that way was the work of Jaak Panksepp, my other scientific mentor. In a classical experiment, Panksepp separated puppies from their mothers for 15 minutes. Never more than that because he animals. When puppies lose their mothers, they make a sound which is called 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 pain or when they miss their mothers. And we all how this cry makes us feel inside.
Panksepp and his colleagues then the brain circuits that produce these cries in guinea pigs, and made a startling discovery. That these are the very same that are active when humans feel sad and when they experience depression. these circuits are also part of the brain’s pain that mediates our sensations of physical and mental pain.
But why are we born with terrible gift hardwired into our brains? Well, probably because like pain, mental pain is an alarm system. Its task is to prevent damage. When babies lose their mothers, they hurt and they cry. Which brings their mothers back, and it makes them seek their mothers. In the wild, this is life-saving. Puppies and cannot survive without their mothers.
So now we know why we have mental pain. It the glue that keeps us together in couples, in families and communities. And when someone we love goes away or 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 that and philosophers have been asking for thousands of years.
Does love always hurt? What do think? Does love always hurt? Yes, love always hurts, of course. Because that’s what it’s supposed to do. Mental pain is simply the price, the very high price, that we pay 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 mental pain. Endorphins are released the brain during aerobic exercise or when we’re close to someone we love, and immediately after severe injuries.
And we now what endorphins do, they attach to special receptors in the brain, and the important among them are mu opioid receptors. And just like receptor I worked on in Kandel’s lab, mu opioid are GPCR.
Here’s how they work. Like all GPCRs, mu opioid receptors made of seven spirals or loops that are stacked together, sticking through both sides of the cell membrane. Like this, OK.
And when endorphins attach to mu opioid receptors from the outside, cause them to change their shape. Like this, OK? And triggers a series of events inside the neurons which eventually ease pain.
Now, forget the molecules for a second. When you hug someone you love is suffering from severe physical or mental pain, you actually cause her brain to endorphins. They attach to mu opioid receptors in her synapses turn them on, and they soothe her pain.
And yet, sometimes mental pain gets so intense that no amount of love can soothe it. But medicine powerful drugs that can ease any physical pain. These are the narcotics or opioids like morphine. Narcotics work mainly by mu opioid receptors.
footnote
But if so, can also treat the pain of separation? It was Jaak Panksepp who found the answer. Panksepp gave his puppies a separation experiment tiny, tiny doses of morphine, lower than the doses that are used to treat physical pain, and his puppies immediately stopped crying started playing with each other as if they no miss their mothers.
Let’s go to humans now. When mental pain in humans becomes intense to bear people, some people, will do anything stop it, even try to kill themselves. Indeed, and I’m saying this as clinical psychiatrist, unbearable mental pain is a huge risk factor for suicide.
footnote
But if narcotics treat physical pain, and if they can soothe the mental pain of separation, can 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 were severely suicidal very low doses of a narcotic drug, called buprenorphine, for four weeks.
We discovered that tiny, tiny doses of buprenorphine, which are too low to treat physical pain, helped many of them become less suicidal. But are extremely dangerous drugs. They may cause addiction, and they’re lethal in overdose. In contrast, endorphins are not lethal in overdose, and they’re much less to cause addiction. So narcotics and endorphins probably activate mu opioid receptors in different ways.
Now, if we could find drugs that activate opioid receptors in a way that resembles how endorphins activate them, might be able to treat physical and mental pain without some of the dangerous side effects 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 drugs at the same time. And when this happens, the result may be different from happens when they’re activated by just one drug. So our research team then used molecular computing technologies create a detailed virtual model of the human mu opioid receptor. And then, with the help of programs as molecular docking algorithms, we screened thousands of existing drugs on a virtual model of the receptor.
Eventually, we found a way to teach old dog, that’s the human 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 mu receptor.
I’m not telling you their names, because we still to run many tests and clinical trials before we can be that their combination does exactly what we think it does. But both of these have been around for many, many years, and 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 into our brains. And mental is 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 they work mainly, not exclusively, but mainly by activating mu opioid receptors.
Now, narcotics also activate mu opioid receptors, but in a way that addiction and can lead to death. And this is narcotics are so dangerous. New computational technologies have helped us identify two existing drugs that may treat physical and mental pain without some of severe side effects of narcotics. However, this is still a work in progress. would be a few years before it may become approved treatment.
But, and this is the last thing I’m going to say, regardless of drugs, you have the ability to family and friends who are in severe physical or mental pain.
Thank you much.
(Applause)
Footnotes
note
“Panksepp gave his puppies, in a 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 their mothers.”
According to results from this 1978 study, morphine-treated puppies were quite alert and moved 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 significant risk factor for suicide, see here.
note
“A few years ago, together with Panksepp and colleagues, my 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 doses of buprenorphine, which are too low to treat physical pain, help many them become less suicidal.”
For more information about these study results, see here.
note
“Some GPCRs can be activated two different drugs at the same time. And when this happens, the result may be for what happens when they’re activated by just one drug.”
For more information about how GPCRs may be activated by different drugs at the same time, see here.