I’m Yoram Youvel. I’m a psychiatrist and neuroscientist at the Hebrew University of Jerusalem. And when was 14 years old, my father died. I 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 is dead.” And then I felt it. A pain in my 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 you felt when someone broke your heart? When your best friend or your mother died? Or the man you loved told you he doesn’t love you anymore. You probably do.
But why do we feel mental pain all? And what’s the relationship between physical and mental pain? And most importantly, how can we make pain better? Together with many scientists and physicians, I spent years searching for answers to these questions.
Now, growing up, I heard the words, “We want you to be a and a brain scientist like your father.” But somehow that’s what happened. Twelve after my father died, I was a graduate student at Dr. Eric Kandel’s lab at Columbia University. Eric, who won the Nobel Prize for his work on the molecular basis of memory, was ultimate mentor. Passionate, energetic and inspiring.
Under his guidance, I studied receptor. It’s a protein that’s part of a synapse. And synapses are structures through which cells communicate with each other. Now that receptor was a GPCR. That’s a G protein coupled receptor. I’ll what this means in a minute and then you’ll understand what this stack markers is doing here.
And when I did that, I didn’t realize that work on that receptor, which seemed completely unrelated to my future work as clinical psychiatrist, would one day help us in our search for better treatments for physical and pain.
Now a big step along that way was the of Jaak 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 make a sound which is the separation distress cry. And it goes like this.
(Imitates puppy wailing)
Puppies it, kittens do it, babies do it. All young mammals do it when they’re in pain or when they miss mothers. And we all know how this cry makes us feel inside.
Panksepp and his colleagues then traced brain circuits that produce these cries in guinea pigs, and they a startling discovery. That these are the very same circuits that are active when humans feel sad and when they experience depression. And these circuits also part of the brain’s pain matrix that mediates our sensations of physical and mental pain.
But why are born with this terrible gift hardwired into our brains? Well, probably because like any pain, mental is an alarm system. Its task is to prevent damage. When babies lose their mothers, they hurt and they cry. Which 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 mental pain. It is the glue that keeps us together in couples, in families and communities. And someone we love goes away or is taken away us, it’s this pain which draws us back together. And once we realize this, then we can an age-old question that poets and philosophers have been asking for of years.
Does love always hurt? What do you think? Does always hurt? Yes, love always hurts, of course. Because that’s it’s supposed to do. Mental 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, think 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 physical and pain. Endorphins are released in the brain during aerobic exercise or when we’re close to someone we love, immediately after severe injuries.
And we now know what endorphins do, they attach to special receptors in the brain, and the most important among them are mu opioid receptors. just like the receptor I worked on in Kandel’s lab, mu opioid receptors are GPCR.
Here’s they work. Like all GPCRs, mu opioid receptors are made seven spirals or loops that are stacked together, sticking through sides of the cell membrane. Like this, OK.
And when endorphins attach 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 the pain.
Now, forget the molecules a second. When you hug someone you love who is suffering from severe physical or pain, you actually cause her brain to release endorphins. They attach to mu 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 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? was Jaak Panksepp who found the answer. Panksepp gave his in a separation experiment tiny, tiny doses of morphine, lower than the lowest doses that are used treat physical pain, and his puppies immediately stopped crying and started playing each other as if they no longer miss their mothers.
Let’s go to now. When mental pain in humans becomes too intense to bear people, some people, will anything to stop it, even try to kill themselves. Indeed, I’m saying this as a 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, they also help suicidal people become less suicidal? A few years ago, with Panksepp and other colleagues, my research team conducted a clinical trial. We gave people who were suicidal very low doses of a narcotic drug, called buprenorphine, for four weeks.
We discovered that tiny, tiny of buprenorphine, which are too low to treat physical pain, helped many of them become suicidal. But narcotics 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 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 in a way that resembles how 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 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. 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 opioid receptor. And then, with the of programs known as molecular docking algorithms, we screened thousands of existing on a virtual model of the receptor.
Eventually, we found a way to teach an old dog, that’s human mu opioid receptor, some new tricks. We found two drugs that are not narcotics, and they together in very, very small doses to activate the human mu opioid receptor.
I’m not telling you names, because we still have to run many tests and trials before we can be certain that their combination 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 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 into our brains. And pain is an essential part of mourning and depression and sadness. And when gets severe enough, it can actually make people suicidal. Endorphins are brain’s natural remedy for physical and pain, and they work mainly, not exclusively, but mainly by activating mu opioid receptors.
Now, narcotics activate mu opioid receptors, but in a way that addiction and can lead to death. And this is why narcotics are so dangerous. New computational technologies have helped us identify existing drugs that together may treat physical and mental pain without of the severe side effects of narcotics. However, this is still work in progress. It would be a few years before it may become an approved treatment.
But, and this is the last thing I’m going say, regardless of drugs, you have the ability to help family and friends who in severe physical or 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 physical pain. And his puppies immediately stopped crying and started with each other as if they no longer miss their mothers.”
According results from this 1978 study, morphine-treated puppies were quite alert and about normally while isolated from their mothers.
note
“Unbearable mental is a huge risk factor for suicide.”
For more information about why mental pain is significant risk factor for suicide, see here.
note
“A few years ago, with Panksepp and other colleagues, my research team conducted a clinical trial. We gave who were severely suicidal, very low doses of a narcotic drug, buprenorphine car buprenorphine four weeks. We discovered that tiny, tiny doses of buprenorphine, which too low to treat physical pain, help many of them less suicidal.”
For more information about these study results, see here.
note
“Some can be activated by 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 two drugs at the same time, see here.