I’m Yoram Youvel. I’m a psychiatrist and neuroscientist at the Hebrew University of Jerusalem. And when I 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 said. “Your father is dead.” And then I felt it. A crushing pain in my chest. I still feel a glimpse of it whenever I think of my father.
He was 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 pain you felt when someone broke your heart? When your best 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 physical and pain? And most importantly, how can we make mental pain better? Together with many scientists physicians, I spent years searching for answers to these questions.
Now, up, I never heard the words, “We want you to be a and a brain scientist like your father.” But somehow that’s what happened. Twelve years after my father died, I was a student at Dr. Eric Kandel’s lab at Columbia University. Eric, who won the Nobel Prize his work on the molecular basis of memory, was the ultimate mentor. Passionate, energetic and inspiring.
Under guidance, I studied a receptor. It’s a protein that’s part of a synapse. And synapses are structures through which nerve cells communicate with each other. Now that receptor was GPCR. That’s a G protein coupled receptor. I’ll explain what this means in a minute then you’ll understand what this stack of markers is doing here.
And when I did that, I didn’t really 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 way was the work 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 sound which is called the separation distress cry. And it goes like this.
(Imitates puppy wailing)
Puppies it, kittens do it, babies do it. All young mammals do when they’re in pain or when they miss their mothers. And we all know how this makes us feel inside.
Panksepp and his colleagues then traced the brain circuits that these cries in guinea pigs, and they made a startling discovery. That these are the very same circuits that are 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 born this terrible gift hardwired into our brains? Well, probably because like 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. Puppies and babies cannot survive without their mothers.
So we know why we have mental pain. It is the glue that 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 realize this, then we can answer an age-old that poets and philosophers have been asking for thousands of years.
Does love always hurt? What do you think? Does love hurt? Yes, love always hurts, of course. Because that’s what it’s to do. Mental pain is simply the high price, the very price, that we pay for our ability to love. personally, and, you know, I’ve been around the block a couple of times, personally, I think it’s worth it.
But we’re not defenseless against pain because our brains produce endorphins or endogenous opioids, our very own feel-good molecules, the natural for both physical and mental pain. Endorphins are released in the brain during exercise or when we’re close to someone we love, and immediately after injuries.
And we now know what endorphins do, they attach to special in the brain, and the most important among them are mu opioid receptors. And just like 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 or loops that are stacked together, sticking through both sides of the cell membrane. Like this, OK.
And endorphins attach to mu opioid receptors from the outside, they cause them to change their shape. Like this, OK? And this triggers a series of events inside the neurons which eventually ease the pain.
Now, forget the for a second. When you hug someone you love who is suffering from physical or mental pain, you actually cause her brain to release endorphins. They attach to mu opioid receptors in her synapses and turn them on, and they soothe pain.
And yet, sometimes mental pain gets so intense that no amount of love soothe it. But medicine has powerful drugs that can ease any physical pain. These are the narcotics or opioids like morphine. Narcotics work 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 doses that are used to treat physical pain, and his immediately stopped crying and started playing with each other as if they longer miss their mothers.
Let’s go to humans now. When pain in humans becomes too intense to bear people, some people, will do anything to stop it, try to kill themselves. Indeed, and I’m saying this as a clinical psychiatrist, unbearable mental pain is a huge risk factor for suicide.
footnote
if narcotics treat physical pain, and if they can soothe the pain of separation, can they also help suicidal people become less suicidal? A few years ago, with Panksepp and other colleagues, my research team conducted a trial. We gave people who were severely suicidal very low 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 are extremely dangerous drugs. may cause addiction, and they’re lethal in 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 in different ways.
Now, if we could find drugs that activate mu opioid receptors a way that resembles how endorphins activate them, we might 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 suddenly remembered what had learned in Kandel’s lab many, many years ago.
footnote
Some GPCRs can be activated by two different drugs at the same time. And this happens, the result may be different from what happens when they’re by just one drug. So our research team then used molecular computing technologies to create a detailed virtual 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 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 doses to activate the human mu opioid receptor.
I’m 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 around for many, many years, and they’ve been used by millions of people. So we know that they’re safe humans.
Here’s our bottom line. Let’s summarize what we’ve seen. and foremost, mental pain is real. It’s hardwired into our brains. And mental pain an essential part of mourning 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 they work mainly, not exclusively, but mainly by activating mu receptors.
Now, narcotics also activate mu opioid receptors, but 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 narcotics. However, this is still a work in progress. It be a few years before it may become an approved treatment.
But, and this is last thing I’m going to say, regardless of drugs, have the ability to help family and friends who are in severe or mental pain.
Thank you very much.
(Applause)
Footnotes
note
“Panksepp gave his puppies, a separation experiment, tiny, tiny doses of morphine – lower than the lowest that are used to treat physical pain. And his puppies immediately stopped crying and 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 normally while isolated from their mothers.
note
“Unbearable mental pain a huge risk factor for suicide.”
For more information about mental pain is a significant risk factor for suicide, see here.
note
“A few years ago, together with Panksepp other colleagues, my research team conducted a clinical trial. We gave people who severely suicidal, very low doses of a narcotic drug, buprenorphine car buprenorphine for four weeks. We that tiny, tiny doses of buprenorphine, which are too low to treat pain, help many of them become less suicidal.”
For more information about these study results, here.
note
“Some GPCRs can be activated by two different drugs at the same time. And when happens, the result may be different for what happens when they’re activated by just one drug.”
For more about how GPCRs may be activated by two different drugs the same time, see here.