I’m Yoram Youvel. I’m a 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 said. “Your father is dead.” And then I felt it. A crushing pain in chest. I can 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. And his death my 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 he doesn’t love you anymore. You probably do.
But do we feel mental pain at all? And what’s the relationship between physical and mental pain? 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 want you to be a doctor and a 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 at Columbia University. Eric, who won the Nobel Prize for his work on molecular basis of memory, was 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 are structures through which nerve cells communicate with each other. that receptor was a GPCR. That’s a G protein coupled receptor. I’ll explain 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 really realize that work on that receptor, which seemed completely unrelated 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, other great scientific mentor. In a classical experiment, Panksepp separated puppies from their mothers for 15 minutes. Never 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 do it, kittens do it, babies it. All young mammals do it when they’re in pain or when they miss their mothers. And we 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 made a startling discovery. That these are very 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 physical and mental pain.
But why are we born 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 they cry. Which brings their mothers back, and it also makes them seek their mothers. In the wild, this is life-saving. Puppies and babies cannot survive without mothers.
So now we know why we have mental pain. It is the glue that keeps us together in couples, in and communities. And when someone we love goes away or is 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 poets and philosophers been asking for thousands of years.
Does love always hurt? What you think? Does love always hurt? Yes, love always hurts, of course. Because that’s what it’s supposed to do. pain is 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 times, personally, I think it’s worth it.
But we’re not entirely defenseless against pain because brains produce endorphins or endogenous opioids, our very own feel-good molecules, the remedy for both physical and mental pain. Endorphins are in the brain during aerobic exercise or when we’re close to someone we love, and immediately after severe injuries.
And we know what endorphins do, they attach to special receptors in the brain, and the most among them are mu opioid receptors. And just like the receptor I worked on in Kandel’s lab, mu receptors are GPCR.
Here’s how they work. Like all GPCRs, mu opioid receptors are made of 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, they them to change their shape. Like this, OK? And this triggers a series of events inside the which eventually ease the pain.
Now, forget the molecules for a second. When hug someone you love who is 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 on, and they soothe her pain.
And yet, sometimes mental gets so intense that no amount of love can soothe it. But medicine has drugs that can ease any physical pain. These are the narcotics or like morphine. Narcotics work mainly by activating mu opioid receptors.
footnote
But if so, can narcotics also treat the pain of separation? It was Panksepp who found the answer. Panksepp gave his puppies in a separation experiment tiny, tiny doses of morphine, than the lowest doses that are used to treat physical pain, and puppies immediately stopped crying and started playing with each as if they no longer miss their mothers.
Let’s go to humans now. When mental pain in becomes too intense to bear people, some people, will do anything to stop it, even to kill themselves. Indeed, and I’m saying this as a clinical psychiatrist, unbearable mental pain is huge risk factor for suicide.
footnote
But if narcotics physical pain, and if they can soothe the mental pain of separation, can they also help suicidal people become suicidal? A few years ago, together with Panksepp and other colleagues, my research 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 extremely dangerous drugs. They may addiction, and they’re lethal in overdose. In contrast, endorphins not lethal in overdose, and they’re much less likely to addiction. So narcotics and endorphins probably activate mu opioid receptors in different ways.
Now, if we could drugs that activate mu opioid receptors in a way that how endorphins activate them, we might be able to physical and mental pain without some of the dangerous side effects narcotics. And when my research team came to this conclusion, I remembered what I 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 when they’re activated 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 known as molecular docking algorithms, we screened of existing drugs on a virtual model of the receptor.
Eventually, we found a way to an old dog, that’s the human mu opioid receptor, some new tricks. We found drugs that are not narcotics, and they work together in 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 trials before we can be that 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 millions of people. So we know that they’re safe for humans.
Here’s our bottom line. Let’s summarize what we’ve seen. First and foremost, mental is real. It’s hardwired into our brains. And mental pain is an essential part mourning and depression and sadness. And when it gets enough, it can actually make people suicidal. Endorphins are brain’s natural for physical and mental pain, and they work mainly, exclusively, but mainly by activating mu opioid receptors.
Now, narcotics also activate mu opioid receptors, but in a way that causes and can lead to death. And this is why narcotics are so dangerous. New computational technologies helped us identify two existing drugs that together may treat and mental pain without some of the severe side effects of narcotics. However, this still a work in progress. It would be a few years it may become an approved treatment.
But, and this is the thing I’m going to say, regardless of drugs, you have the ability to help family and friends who are in severe physical or mental pain.
Thank you much.
(Applause)
Footnotes
note
“Panksepp gave his puppies, in a separation experiment, tiny, tiny 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 to from this 1978 study, morphine-treated puppies were quite alert and moved about normally while isolated from their mothers.
note
“Unbearable mental pain is a huge risk factor for suicide.”
For more information why mental pain is a significant risk factor for suicide, see here.
note
“A few years ago, together with and other colleagues, my research team conducted a clinical trial. We gave people who were severely suicidal, very low doses a narcotic drug, buprenorphine car buprenorphine for four weeks. We discovered that tiny, tiny of buprenorphine, which are too low to treat physical pain, help many of 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, result may be different for what happens when they’re activated by just drug.”
For more information about how GPCRs may be activated by two different drugs at same time, see here.