I’m Youvel. I’m a psychiatrist and neuroscientist at the Hebrew University of Jerusalem. when I was 14 years old, my father died. I was sitting in class when mother and my grandfather knocked on the door and asked out to the corridor.
“Your father’s very sick,” my mother said. “Your father is dead.” And then I felt it. A crushing pain in my chest. can still feel a glimpse of it whenever I of my father.
He was a doctor, a scientist, a paratrooper. He was a young, strong, happy, healthy man. was my hero. And his death broke my heart.
Do you remember the you felt when someone broke your heart? When your best friend or your mother died? Or the man you loved told you that he doesn’t love you anymore. You probably do.
But why do feel mental pain at all? And what’s the relationship between and mental pain? And most importantly, how can we make mental pain better? Together many scientists and physicians, I spent years searching for answers to these questions.
Now, growing up, I never the words, “We want you to be a doctor and a brain like your father.” But somehow that’s what happened. Twelve years after my father died, I was a graduate student at Dr. 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 his guidance, I studied a receptor. It’s a protein that’s of a synapse. And synapses 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 means in a minute and then you’ll understand what this stack of markers doing here.
And when I did that, I didn’t really realize work on that receptor, which seemed completely unrelated to my future work as a clinical psychiatrist, would day help us in our search for better treatments for physical and mental pain.
Now a big step that way was the work of Jaak Panksepp, my other scientific mentor. In a classical experiment, Panksepp separated puppies from their for 15 minutes. Never more than that because he loved animals. When puppies lose their mothers, they make a which is called the separation distress cry. And it goes like this.
(Imitates puppy wailing)
Puppies do it, kittens do it, babies do it. All mammals do it 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 produce these cries in guinea pigs, and they made a discovery. That these are the very same circuits that are active when humans feel sad and when experience depression. And these circuits are also part of the brain’s pain 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 an alarm system. Its task is prevent damage. When babies lose their mothers, they hurt and cry. Which brings their mothers back, and it also makes them seek their mothers. In the wild, this is life-saving. Puppies babies cannot survive without their mothers.
So now we know why we have mental pain. is the glue that keeps us together in couples, in families and communities. when someone we love goes away or is taken away from us, it’s pain which draws us back together. And once we realize this, then we can an age-old question that poets and philosophers have been asking for thousands of years.
Does love always hurt? do 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, know, I’ve been around the block a couple of times, personally, I think it’s worth it.
But we’re not entirely defenseless against pain because our brains produce 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 after severe injuries.
And we now know what endorphins do, they attach to special receptors in the brain, and the most important among them are mu opioid receptors. And just like the I worked on in Kandel’s lab, mu opioid receptors are GPCR.
Here’s how they work. Like all GPCRs, mu receptors are made of seven spirals or loops that are stacked together, sticking through both sides of the cell membrane. this, OK.
And when endorphins attach to mu opioid receptors from the outside, they cause them to change shape. Like this, OK? And this triggers a series of events inside the neurons which ease the pain.
Now, forget the molecules for a second. When you someone you love who is suffering from severe physical mental pain, you actually cause her brain to release endorphins. They attach to opioid receptors in her synapses and turn them on, and they soothe her pain.
And yet, sometimes mental pain gets so that no amount of love can soothe it. But medicine has powerful drugs that can ease 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. gave his puppies in a separation experiment tiny, tiny doses of morphine, lower than the lowest doses that are to treat physical pain, and his puppies immediately stopped crying and started playing with each other as if they no longer miss their mothers.
Let’s go to now. When mental pain in humans becomes too intense to people, some people, will do anything to stop it, even 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, they also help suicidal people become less suicidal? A few years ago, together with Panksepp and other colleagues, my team conducted a clinical 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 cause addiction, and they’re lethal in overdose. In contrast, endorphins are lethal in overdose, and they’re much less likely to cause addiction. So narcotics endorphins 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 treat physical and mental pain without some of the dangerous side effects of narcotics. And when my team came to this conclusion, I suddenly remembered what I had learned Kandel’s lab many, many years ago.
footnote
Some GPCRs can be activated by two different at the same time. And when this happens, the result may different from what happens when they’re activated by just one drug. So our research team then used molecular computing to create a detailed virtual model of the human opioid receptor. And then, with the help of programs known as docking algorithms, we screened thousands of existing drugs on a model of the receptor.
Eventually, we found a way to teach an old dog, that’s human mu opioid receptor, some new tricks. We found drugs that are not narcotics, and they work together in very, very small doses activate the human mu opioid receptor.
I’m not telling you their names, we still have to run many tests and clinical trials we can be certain that their combination does exactly what we think it does. But both of these have been around for many, many years, and they’ve been used by millions 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 into our brains. And mental pain is an essential part of mourning and depression and sadness. And when it gets enough, it can actually make people suicidal. Endorphins are brain’s natural remedy for physical and pain, and they work mainly, not exclusively, but mainly by activating mu receptors.
Now, narcotics also activate mu opioid receptors, but in a that causes addiction and can lead to death. And this is why narcotics are so dangerous. New computational technologies have us identify two existing drugs that together may treat physical mental pain without some of the severe side effects narcotics. However, this is still a work in progress. It would be few years before it may become an approved treatment.
But, and this is the last thing I’m going to say, of drugs, you have the ability to help family and friends who in severe physical or mental pain.
Thank you very much.
(Applause)
Footnotes
note
“Panksepp his puppies, in a separation experiment, tiny, tiny doses of morphine – lower than the lowest doses that are used to treat pain. And his puppies immediately stopped crying and started 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 pain is a huge risk factor for suicide.”
For more information about why mental pain is a risk factor for suicide, see here.
note
“A few years ago, together with Panksepp and other colleagues, my research team conducted a clinical trial. We gave people were severely suicidal, very low doses of a narcotic drug, buprenorphine buprenorphine for four weeks. We discovered that tiny, tiny doses 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 two different drugs at the same time. And when happens, the result may be different for what happens they’re activated by just one drug.”
For more information how GPCRs may be activated by two different drugs the same time, see here.