I’m Yoram Youvel. I’m a psychiatrist and neuroscientist at the Hebrew University of Jerusalem. And I was 14 years old, my father died. I was sitting in class when my mother and my grandfather knocked on the door and me out to the corridor.
“Your father’s very sick,” mother said. “Your father is dead.” And then I felt it. A crushing pain in my chest. I can still feel a glimpse of it whenever think of my father.
He was a doctor, a scientist, paratrooper. He was a young, strong, happy, healthy man. was my hero. And his death broke my heart.
Do remember the pain you felt when someone broke your heart? When your best friend or your died? Or the man you loved told you that he doesn’t love you anymore. 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 make mental pain better? Together with many scientists and physicians, I spent searching for answers to these questions.
Now, growing up, I never 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 at Dr. Eric Kandel’s lab at Columbia University. Eric, who won the Nobel for his work on the molecular basis of memory, was ultimate mentor. Passionate, energetic and inspiring.
Under his guidance, I a receptor. It’s a protein that’s part of a synapse. And synapses structures through which nerve cells communicate with each other. Now that receptor was a GPCR. That’s a protein coupled receptor. I’ll explain what this means in a minute and then you’ll understand what 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 future as a clinical psychiatrist, would one day help us in our for better treatments for physical and mental pain.
Now a step along that way was the work of Jaak Panksepp, my other great scientific mentor. In a classical experiment, separated puppies from their mothers for 15 minutes. Never more than because he loved animals. When puppies lose their mothers, they make a sound is called the separation distress cry. And it goes like this.
(Imitates puppy wailing)
Puppies do it, kittens it, babies do it. All young mammals 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 traced the brain that produce these cries in guinea pigs, and they made a startling discovery. That are the very same circuits that are active when humans feel sad and when they depression. And these circuits are also part of the brain’s pain matrix that mediates our sensations of and mental pain.
But why are we born with this terrible hardwired into our brains? Well, probably because like any 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 them seek their mothers. In the wild, is life-saving. Puppies and babies cannot survive without their mothers.
So we know why we have mental pain. It is the glue that keeps us together couples, in families and communities. And when someone we goes away or is taken away from us, it’s this pain which us back together. And once we realize this, then can answer an age-old question that poets and philosophers have been for thousands of years.
Does love always hurt? What do you think? love always hurt? Yes, love always hurts, of course. Because that’s what it’s supposed do. Mental pain is simply the high price, the very high price, that we pay our ability to love. And personally, and, you know, I’ve been around the block a couple of times, personally, I think it’s worth it.
But we’re entirely defenseless against pain because our brains produce endorphins or endogenous opioids, our very own feel-good molecules, the natural remedy for both physical and mental pain. Endorphins are released in the 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 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 GPCRs, mu opioid receptors are made of seven spirals or loops that are stacked together, sticking through sides of the cell membrane. Like this, OK.
And endorphins attach to mu opioid receptors from the outside, they them to change their shape. Like this, OK? And this triggers a series events inside the neurons which eventually ease the pain.
Now, forget the molecules for a second. When you hug you love who is suffering from severe physical or mental pain, you actually cause her brain to release endorphins. They attach to mu opioid receptors in her synapses turn them on, and they soothe her 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 narcotics or opioids like morphine. Narcotics work mainly by activating mu opioid receptors.
footnote
But if so, narcotics also treat the pain of separation? It was Jaak Panksepp who found the answer. Panksepp 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 other as if they no longer their mothers.
Let’s go to humans now. When mental pain humans becomes too intense to bear people, some people, will do anything to stop it, even try to kill themselves. Indeed, and I’m saying this as a clinical psychiatrist, unbearable mental is a huge risk factor for suicide.
footnote
if narcotics treat physical pain, and if they can 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 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 of buprenorphine, which are too low treat physical pain, helped many of them become less suicidal. But narcotics are extremely dangerous drugs. They may cause addiction, and they’re in overdose. In contrast, endorphins are not lethal in overdose, and they’re much less likely to cause addiction. So narcotics and probably activate mu opioid receptors in different ways.
Now, if we could find drugs that activate mu receptors in a way that resembles how endorphins activate them, we might be able to 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 different drugs at the same time. And when this happens, result may be different from what happens when they’re activated just one drug. So our research team then used molecular computing technologies to a detailed virtual model of the human mu opioid receptor. And then, with the help of programs known as docking algorithms, we screened thousands of existing drugs on a virtual model of the receptor.
Eventually, we found a way to teach an old dog, that’s the human mu opioid receptor, some new tricks. We found two drugs are not narcotics, and they work together in very, very small doses to the human mu opioid receptor.
I’m not telling you their names, because still have to run many tests and clinical trials before we be certain 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 of people. So we know that they’re safe for humans.
Here’s bottom line. Let’s summarize what we’ve seen. First and foremost, mental pain is real. It’s hardwired into our brains. And mental pain is an essential part of mourning and depression and sadness. And when it gets severe enough, it can actually make people suicidal. Endorphins are brain’s natural remedy for and mental 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 causes addiction and can lead to death. this is why narcotics are so dangerous. New computational technologies have helped us identify two drugs that together may treat physical and mental pain without some of the severe effects of narcotics. However, this is still a work in progress. It would be a few before it may become an approved treatment.
But, and is the last thing I’m going to say, regardless of drugs, you have the ability to help family and friends who are in physical or mental pain.
Thank you very much.
(Applause)
Footnotes
note
“Panksepp gave his puppies, in a experiment, tiny, tiny doses of morphine – lower than the lowest that are used to treat physical pain. And his puppies immediately crying and started 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 while isolated from their mothers.
note
“Unbearable mental is a huge risk factor for suicide.”
For more information about mental pain is a significant risk factor for suicide, see here.
note
“A years ago, together 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, buprenorphine car buprenorphine for four weeks. We discovered that tiny, tiny doses of buprenorphine, are too low to treat physical pain, help many of them become less suicidal.”
For more information these study results, see here.
note
“Some GPCRs can be by two different drugs at the same time. And when this happens, the result be different for what happens when they’re activated by just one drug.”
For information about how GPCRs may be activated by two different drugs at the same time, see here.