I’m Yoram Youvel. I’m a psychiatrist and neuroscientist at the Hebrew University of Jerusalem. And when I was 14 years old, my father died. I was sitting in class when my mother and my grandfather knocked on the door and asked me out to the corridor.
“Your father’s sick,” my mother said. “Your father is dead.” And then I felt it. A crushing pain in my chest. I can still feel a of it whenever I think of my father.
He was a doctor, a scientist, a paratrooper. He was a young, strong, happy, healthy man. He was my hero. And his death broke heart.
Do you remember the pain you felt when broke your heart? When your best friend or your died? Or the man you loved told you that doesn’t love you anymore. You probably do.
But why do we feel mental pain at all? And what’s the relationship physical and mental pain? And most importantly, how can we mental pain better? Together with many scientists and physicians, 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 scientist like your father.” But somehow that’s what happened. Twelve years after my father died, I was a graduate student Dr. Eric Kandel’s lab at Columbia University. Eric, who won Nobel Prize for his work on the molecular basis of memory, 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 synapses are 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 in a minute and then you’ll understand what this stack of markers is doing here.
And when I did that, I didn’t really realize that work on that receptor, which seemed completely unrelated to my work as a clinical psychiatrist, would one day help us in search for better treatments for physical and mental pain.
Now a big step along that way 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 loved animals. When puppies lose their mothers, they make a sound which called the 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 pain or when they miss their mothers. And we know how this cry makes us feel inside.
Panksepp and his colleagues then traced the brain circuits that produce these cries in guinea pigs, and they made a startling discovery. That these the very same circuits that are active when humans feel sad when they experience depression. And these circuits are also part of the brain’s pain matrix that 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, pain is an alarm system. Its task is to prevent damage. When babies lose 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 know why we have mental pain. It is the glue keeps us together in couples, in families and communities. And when someone we love goes away is taken away from us, it’s this pain which draws us back together. And once we realize this, then we answer an age-old question that poets and philosophers have been asking for thousands of years.
Does love hurt? What do you think? Does love always hurt? Yes, love hurts, of course. Because that’s what it’s supposed to do. Mental pain simply the high price, the very high price, that we pay for our ability to love. And personally, and, you know, I’ve been around the block a couple of times, personally, I think it’s it.
But we’re not entirely defenseless against pain because our produce endorphins or endogenous opioids, our very own feel-good molecules, the natural remedy for both physical and mental pain. Endorphins are released in brain during aerobic exercise or when we’re close to someone we love, and immediately after severe injuries.
And we now know what endorphins do, attach to special receptors in the brain, and the most important among them are mu opioid receptors. And just the receptor I worked on in Kandel’s lab, mu opioid receptors are GPCR.
Here’s how they work. Like all GPCRs, mu opioid receptors are made of seven spirals or that are stacked together, sticking through both sides of the membrane. Like this, OK.
And when endorphins attach to mu opioid receptors from outside, they cause them to change their shape. Like this, OK? And triggers a series of events inside the neurons which eventually ease the pain.
Now, forget molecules for a second. When you hug someone you love who 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 pain gets so intense that no amount of love soothe it. But medicine has powerful drugs that can ease any physical pain. are the narcotics or opioids like morphine. Narcotics work by activating mu opioid receptors.
footnote
But if so, can narcotics also treat the of separation? It was Jaak Panksepp who found the answer. Panksepp gave his puppies in a separation experiment tiny, doses of morphine, 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.
Let’s to humans now. When mental pain in humans becomes intense to bear people, some people, will do anything to stop it, even try to themselves. Indeed, and I’m saying this as a clinical psychiatrist, unbearable mental pain is a huge factor for suicide.
footnote
But if narcotics treat physical pain, and if they soothe the mental pain of separation, can they also help suicidal people become less suicidal? A few years ago, together with and other colleagues, my research team conducted a clinical trial. We gave people who severely suicidal very low doses of a narcotic drug, called buprenorphine, for weeks.
We discovered that tiny, tiny doses of buprenorphine, which are too low treat physical pain, helped many of them become less suicidal. But narcotics are dangerous drugs. They may cause addiction, and they’re lethal overdose. In contrast, endorphins are not lethal in overdose, and they’re less likely to cause addiction. So narcotics and endorphins probably activate mu opioid receptors in different ways.
Now, we could find drugs that activate mu opioid receptors a way that resembles how endorphins activate them, we might be able to treat physical and mental pain 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 years ago.
footnote
Some GPCRs can be by two different drugs at the same time. And when happens, the result may be different from what happens when they’re activated by just one drug. So our research team then used computing technologies to create a detailed virtual model of the human mu receptor. And then, with the help of programs known molecular docking algorithms, we screened thousands of existing drugs on a virtual model of the receptor.
Eventually, we found way to teach an 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 their names, because we still have to run many tests and clinical before we can be certain that their combination does exactly we think it does. But both of these drugs have 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 pain is an essential part of mourning and depression and sadness. And it gets severe enough, it can actually make people suicidal. Endorphins are brain’s natural remedy for physical and mental pain, and they work mainly, not exclusively, but mainly by activating mu receptors.
Now, narcotics also activate mu opioid receptors, but in a way causes addiction and can lead to death. And this why narcotics are so dangerous. New computational technologies have helped identify two existing drugs that together may treat physical and mental pain without some of the severe side effects of narcotics. However, this is still a work progress. It would be a few years before it may 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 who are in severe physical mental pain.
Thank you very much.
(Applause)
Footnotes
note
“Panksepp gave puppies, in a separation experiment, tiny, tiny doses of morphine – lower than the lowest doses that 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 moved about normally while isolated from their mothers.
note
“Unbearable pain is a huge risk factor for suicide.”
For more information about why mental is a significant risk factor for suicide, see here.
note
“A few years ago, together 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 for four weeks. We discovered that tiny, tiny doses of buprenorphine, which are too low to treat physical pain, help many of become less suicidal.”
For more information about these study results, see here.
note
“Some GPCRs can be activated by two different drugs the same time. And when this happens, the result may be different 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.