I’m Yoram Youvel. I’m a psychiatrist and neuroscientist the Hebrew University of Jerusalem. And when I was 14 years old, father died. I was sitting in class when my mother and my grandfather knocked 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 of it whenever I think of my father.
He was a doctor, a scientist, a paratrooper. was a young, strong, happy, healthy man. He was hero. And his death broke my heart.
Do you remember pain you felt when someone broke your heart? When your friend 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 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, spent years searching for answers to these questions.
Now, growing up, I heard the words, “We want you to be a doctor and a brain scientist like your father.” somehow that’s what happened. Twelve years after my father died, I a graduate student at Dr. Eric Kandel’s lab at Columbia University. Eric, who won the Nobel Prize for work on the molecular basis of memory, was the 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 structures through which cells communicate with each other. Now that receptor was a GPCR. That’s a G protein coupled receptor. I’ll explain this means in a minute and then you’ll understand what this of markers is doing here.
And when I did that, I didn’t really realize that work that receptor, which seemed completely unrelated to my future work as a psychiatrist, would one day help us in our search for better treatments for physical mental pain.
Now a big step along that way was the of Jaak Panksepp, my other great scientific mentor. In a classical experiment, Panksepp separated from their mothers for 15 minutes. Never more than because he loved animals. When puppies lose their mothers, they make a sound which is called the separation distress cry. And goes like this.
(Imitates puppy wailing)
Puppies do it, kittens do it, babies do it. All young mammals 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 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 and they experience depression. And these circuits are also part of the brain’s pain matrix that mediates our sensations of physical and mental pain.
But why are we born with this terrible gift into our brains? Well, probably because like any pain, mental pain is alarm system. Its task is to prevent damage. When babies lose their mothers, they and they cry. Which brings their mothers back, and it also them seek their mothers. In the wild, this is life-saving. and babies cannot survive without their mothers.
So now we know we have mental pain. It is the glue that keeps us together in couples, in families and communities. And when we love goes away or is taken away from us, it’s this pain which draws us back together. And we realize this, then we can answer an age-old question that poets and have been asking for thousands of years.
Does love hurt? What do you think? Does love always hurt? Yes, love always hurts, of course. Because that’s what it’s supposed to do. Mental pain 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 couple of times, personally, I think it’s worth it.
But we’re not entirely defenseless against pain because our brains produce endorphins or endogenous opioids, our own feel-good molecules, the natural remedy for both physical and mental pain. Endorphins are released in the brain during aerobic exercise or when we’re to someone we love, and immediately after severe injuries.
And we now know what endorphins do, they attach to special receptors in the brain, and the important among them are mu opioid receptors. And just like the receptor I worked in Kandel’s lab, mu opioid receptors are GPCR.
Here’s how they work. all GPCRs, mu opioid receptors are made of seven spirals 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 them to change their shape. Like this, OK? And this a series of events inside the neurons which eventually ease pain.
Now, forget the molecules for a second. When you hug someone you love who is suffering severe physical or mental pain, you actually cause her to release endorphins. They attach to mu opioid receptors in her synapses and turn them on, and 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 any physical pain. These are the 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 found the answer. Panksepp gave his puppies in a separation experiment tiny, tiny doses of morphine, lower than the lowest doses that are used to 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 humans now. When mental pain in humans too intense to bear people, some people, will do anything stop it, even try to kill themselves. Indeed, and I’m saying this as a clinical psychiatrist, unbearable 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, can they also help suicidal people become suicidal? A few years ago, together with Panksepp and other colleagues, my research team conducted a clinical trial. 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 to physical pain, helped many of them become less suicidal. narcotics are extremely dangerous drugs. They may cause addiction, and they’re lethal in overdose. In contrast, are not lethal in overdose, and they’re much less likely cause addiction. So narcotics and endorphins probably activate mu opioid receptors different ways.
Now, if we could find drugs that activate mu opioid receptors in a way that resembles how endorphins activate them, we might able to treat physical and mental pain without some of dangerous side effects of narcotics. And when my research came 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 this happens, the result may be different from what happens when they’re by just one drug. So our research team then used molecular technologies to create a detailed virtual model of the human mu opioid receptor. then, with the help of programs known as molecular algorithms, we screened thousands of existing drugs on a virtual model of the receptor.
Eventually, we found a way to teach an dog, that’s the human mu opioid receptor, some new tricks. We two drugs that are not narcotics, and they work together in very, very small to activate the human mu opioid receptor.
I’m not telling you their names, because we still have run many tests and clinical trials before we can be certain that their combination does exactly 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 know they’re safe for humans.
Here’s our bottom line. Let’s summarize we’ve seen. First and foremost, mental pain is real. It’s hardwired into our brains. And mental pain is an essential part of and depression and sadness. And when it gets severe enough, can actually make people suicidal. Endorphins are brain’s natural remedy for physical and mental pain, and they work mainly, exclusively, but mainly by activating mu opioid receptors.
Now, narcotics also activate mu receptors, but in a way that causes addiction and can lead to death. And is why narcotics are so dangerous. New computational technologies have helped us identify two existing that together may treat physical and mental pain without some of the severe side effects of narcotics. However, is still a work in progress. It would be a 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 are severe physical or 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 are used to treat physical pain. And his puppies immediately stopped and started playing with each other as if they no miss their mothers.”
According to results from this 1978 study, morphine-treated puppies were quite alert and moved normally while isolated from their mothers.
note
“Unbearable pain is 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 and other colleagues, my research team conducted a trial. We gave people who were severely suicidal, very low doses of a narcotic drug, buprenorphine car buprenorphine for four weeks. We discovered that tiny, tiny doses of buprenorphine, which are too low to treat physical pain, help many of them become less suicidal.”
For more 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 for what happens they’re activated by just one drug.”
For more information about how GPCRs may activated by two different drugs at the same time, see here.