I’m 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 class when my mother and my grandfather knocked on the and asked me out to the corridor.
“Your father’s very sick,” my mother said. “Your father is dead.” then I felt it. A crushing pain in my chest. I can still 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 broke my heart.
Do you remember the pain 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 anymore. You 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 years searching for answers to these questions.
Now, growing up, I never heard the words, “We want you to 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 the Nobel Prize for his work on the molecular of memory, was the ultimate mentor. Passionate, energetic and inspiring.
Under his guidance, I studied 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 what this means in a and then you’ll understand what this stack of markers is doing here.
And I did that, I didn’t really realize that work on that receptor, which seemed completely to my future work as a clinical psychiatrist, would one day help us in our search for better for physical and mental pain.
Now a big step along that way was the work Jaak Panksepp, my other great scientific mentor. In a classical experiment, Panksepp puppies from their mothers for 15 minutes. Never more than that because he loved animals. When puppies lose mothers, they make a sound which is called the separation distress cry. And it like this.
(Imitates puppy wailing)
Puppies do it, kittens do it, babies do it. All young mammals do it when they’re in pain or when they miss their mothers. And we all know how this cry us feel inside.
Panksepp and his colleagues then traced the brain circuits that produce these cries guinea pigs, and they made a startling discovery. That these are the 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 physical and mental pain.
But why are we born with this terrible gift hardwired 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 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 the glue that keeps us together in couples, in families 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 have been asking for thousands of years.
Does always 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 is simply the high price, the very high price, that we pay for ability to love. And personally, and, you know, I’ve been around the block a couple of times, personally, I it’s worth it.
But we’re not entirely defenseless against pain because our brains produce endorphins or endogenous opioids, our very feel-good molecules, the natural remedy for both physical and mental pain. Endorphins are released the brain during aerobic exercise or when we’re close to someone we love, immediately after severe injuries.
And we now know what do, they attach to special receptors in the brain, and the most important among them are mu opioid receptors. And just like receptor I worked on in Kandel’s lab, mu opioid receptors are GPCR.
Here’s how they work. Like all GPCRs, mu opioid are made of seven spirals or loops that are stacked together, sticking through 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 events inside the neurons which eventually ease the pain.
Now, forget the molecules for second. When you 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 them on, and they soothe her pain.
And yet, sometimes mental pain gets so intense that no amount love can 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
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 are used to treat physical pain, and his puppies immediately stopped crying and started playing with each other as if they longer miss their mothers.
Let’s go to humans now. When mental pain in humans becomes too intense to people, some people, will do anything to stop it, even try to kill themselves. Indeed, 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 people become less suicidal? A few years ago, together with and other colleagues, my research team conducted a clinical trial. We gave people who severely suicidal very low doses of a narcotic drug, called buprenorphine, for four weeks.
We discovered that tiny, tiny of buprenorphine, which are too low to treat physical pain, many of them become less suicidal. But narcotics are extremely drugs. They may cause addiction, and they’re lethal in overdose. contrast, endorphins are not 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 mu opioid receptors in a way that resembles how activate them, we might be able to treat physical and mental pain without some of the dangerous side effects narcotics. And when my research team came to this conclusion, I suddenly remembered what I had learned in Kandel’s many, many years ago.
footnote
Some GPCRs can activated by two different drugs at the same time. And when happens, the result may be different from what happens when they’re activated by just drug. So our research team then used molecular computing technologies to create a detailed model of the human mu opioid receptor. And then, the help of programs known as molecular docking algorithms, we screened thousands of existing drugs on virtual model of the receptor.
Eventually, we found a way to teach old dog, that’s the human mu opioid receptor, some new tricks. We found two drugs that not narcotics, and they work together in very, very doses to activate the human mu opioid receptor.
I’m not telling you their names, because we still have to run tests and clinical trials before we can be certain that combination does exactly what we think it does. But of these drugs have been around for many, many years, and they’ve used by 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 pain is real. It’s hardwired into our brains. And mental is an essential part of mourning and depression and sadness. And when it gets severe enough, it can 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 opioid receptors, but in a way that causes addiction and can lead to death. And this 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. would be a few years before it may become an approved treatment.
But, this is the last thing I’m going to say, regardless of drugs, you the ability to help family and friends who are in severe physical or mental pain.
Thank you very much.
(Applause)
Footnotes
note
“Panksepp 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 mothers.”
According to results from this 1978 study, morphine-treated puppies were alert and moved about normally while isolated from their mothers.
note
“Unbearable mental pain is a risk factor for suicide.”
For more information about why mental is a significant risk factor for suicide, see here.
note
“A few years ago, together with Panksepp and colleagues, my research team conducted a clinical trial. We gave people who were severely suicidal, low doses of a narcotic drug, buprenorphine car buprenorphine for four weeks. We discovered that tiny, tiny doses of buprenorphine, which too low to treat physical pain, help many of them 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, the result may different for what happens when they’re activated by just one drug.”
For more information about how GPCRs may activated by two different drugs at the same time, here.