I’m Youvel. I’m a psychiatrist and neuroscientist at the Hebrew University of Jerusalem. And when I was 14 old, my father died. I was sitting in class my mother and my grandfather knocked on the door asked me out to 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 it whenever I think of father.
He was a doctor, a scientist, a paratrooper. He was a young, strong, happy, healthy man. He was hero. And his death broke my heart.
Do you remember the pain you felt when someone your heart? When your best friend or your mother died? Or the man you loved told that he doesn’t love you anymore. You probably do.
But why do feel mental pain at all? And what’s the relationship between physical and mental pain? And most importantly, how can we make mental 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 your father.” But somehow that’s what happened. years after my father died, I was a graduate student at Dr. Eric Kandel’s lab Columbia University. Eric, who won the Nobel Prize for his work on the molecular basis memory, was the ultimate mentor. Passionate, energetic and inspiring.
Under his guidance, I studied a receptor. It’s a protein that’s part a synapse. And synapses are structures through which nerve cells with each other. Now that receptor was a GPCR. That’s G protein coupled receptor. I’ll explain what this means in a minute and then you’ll 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 a clinical psychiatrist, would one day help us in search for better treatments for physical and mental pain.
Now big step along that way was the work of Panksepp, my other great scientific mentor. In a classical experiment, Panksepp separated puppies from their mothers 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 this.
(Imitates puppy wailing)
Puppies do it, kittens do it, babies do it. All young do it when they’re in pain or when they miss their mothers. 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 they experience depression. And these circuits are also of the brain’s pain matrix that mediates our sensations of physical and mental pain.
But why are we with this 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 they 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 their mothers.
So now we 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 or is taken from us, it’s this pain which draws us back together. And once we this, then we can answer an age-old question that poets and philosophers been asking for thousands of years.
Does love always hurt? What do you think? Does love always hurt? Yes, love hurts, of course. Because that’s what it’s supposed to do. pain is simply the high price, the very high price, that pay for our ability to love. And personally, and, you know, I’ve been around the block a couple of times, personally, I it’s worth it.
But we’re not entirely defenseless against pain because our brains produce endorphins endogenous opioids, our very own feel-good molecules, the natural remedy for both and mental pain. Endorphins are released in the brain during aerobic 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 the brain, and the most important among them are mu opioid receptors. And just like the receptor I on in Kandel’s lab, mu opioid receptors are GPCR.
Here’s how they work. Like all GPCRs, mu opioid receptors are of seven spirals or loops that are stacked together, sticking through both 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? And this a series of events inside the neurons which eventually ease pain.
Now, forget the molecules for a second. When you hug someone love who is suffering from 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 pain gets so intense 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 mu opioid receptors.
footnote
But if so, can narcotics also treat the pain separation? It was Jaak Panksepp who found the answer. Panksepp gave his puppies in a separation experiment tiny, tiny doses 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.
Let’s go to humans now. When mental pain in humans becomes too intense bear people, some people, will do anything to stop it, even try to kill themselves. Indeed, I’m saying this as a clinical psychiatrist, unbearable mental pain a huge risk factor for suicide.
footnote
But if narcotics treat physical pain, and they can soothe the mental pain of separation, can they also help people become less suicidal? A few years ago, together with and other colleagues, my research team conducted a clinical trial. We gave people who were severely very low doses of a narcotic drug, called buprenorphine, for four weeks.
We discovered that tiny, tiny doses of buprenorphine, are too low to treat physical pain, helped many of them become less suicidal. But narcotics are 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 likely cause addiction. So narcotics and endorphins probably activate mu opioid receptors in different 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 treat and mental pain without some of the dangerous side effects of narcotics. And when my research team came to this conclusion, suddenly remembered what I had learned in Kandel’s lab 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 when they’re activated by just one drug. So our research team then used molecular computing to create a detailed virtual model of the human mu opioid receptor. And then, with the help of programs known 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 drugs that are not narcotics, and they work together 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 that their combination does exactly what we think it does. both of these drugs have been around for many, many years, and they’ve been used by millions of people. 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 is real. It’s hardwired our brains. And mental pain is an essential part of and depression and sadness. And when it gets severe enough, it can actually make suicidal. Endorphins 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 a way that addiction and can lead to death. And this is why narcotics so dangerous. New computational technologies have helped us identify two existing drugs that together may treat physical mental pain without some of the severe side effects narcotics. However, this is still a work in progress. It would be a few years before it may become an approved treatment.
But, 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 puppies, 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 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 about normally isolated from their mothers.
note
“Unbearable mental pain is huge risk factor for suicide.”
For more information about why mental pain is a significant risk factor 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, buprenorphine car buprenorphine for weeks. We discovered that tiny, tiny doses of buprenorphine, which are too low to treat physical pain, help many of them become less suicidal.”
For more information about these results, see here.
note
“Some GPCRs can be activated by two different drugs at 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 be activated by two different drugs at the same time, see here.