I’m Youvel. I’m a psychiatrist and neuroscientist at the Hebrew of Jerusalem. And when I was 14 years old, my father died. was sitting in class when my mother and my grandfather knocked on the door and asked me to the corridor.
“Your father’s very sick,” my mother said. “Your 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, 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 someone your heart? When your best friend or your mother died? Or the man you loved told you he doesn’t love you anymore. You probably do.
But why we 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 with many scientists and physicians, I spent searching for answers to these questions.
Now, growing up, I never heard the words, “We want you be a doctor and a brain scientist like your father.” But somehow that’s what happened. Twelve years after father died, I was a graduate student at Dr. Eric Kandel’s lab at Columbia University. Eric, won the Nobel Prize for his work on the molecular basis of memory, was the ultimate mentor. Passionate, energetic inspiring.
Under his guidance, I studied a receptor. It’s protein that’s part of a synapse. And synapses are through which nerve cells communicate with each other. Now that receptor was a GPCR. That’s a G coupled receptor. I’ll explain what 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 on that receptor, seemed completely unrelated to my future work as a clinical psychiatrist, would one day help us in our for better treatments 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 separated puppies from their mothers for 15 minutes. Never more than that he loved animals. When puppies lose their mothers, they make sound which is called the separation distress cry. And it goes 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 mothers. And we all know how this cry makes feel inside.
Panksepp and his colleagues then traced the brain circuits that produce these cries in guinea pigs, they made a startling discovery. That these are the very circuits that are active when humans feel sad and when they experience depression. these circuits are also part of the brain’s pain matrix mediates our sensations of physical and mental pain.
But why are we born with this terrible gift hardwired into brains? Well, probably because like any pain, mental pain is an alarm system. Its is to prevent damage. When babies lose their mothers, hurt and they cry. Which brings their mothers back, and it also makes seek their mothers. In the wild, this is life-saving. Puppies and babies cannot survive without their mothers.
So now we why we have mental pain. It is the glue that keeps us together in couples, in families and communities. And when someone we love goes away or is away from us, it’s this pain which draws us back together. And once we realize this, then we can answer an age-old question poets and philosophers have been asking for thousands of years.
Does love 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 pain is the high price, the very high price, that we for our ability to love. And personally, and, you know, I’ve been around the block a couple of times, personally, 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 natural for both physical and mental pain. Endorphins are released in the brain during aerobic exercise or when we’re close to someone we love, and after severe injuries.
And we now know what endorphins do, they to special receptors in the brain, and the most important them are mu opioid receptors. And just like the receptor worked on in Kandel’s lab, mu opioid receptors are GPCR.
Here’s how they work. Like all GPCRs, mu opioid receptors are made of seven spirals or 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, cause them to change their shape. Like this, OK? And this a series of events inside the neurons which eventually ease the pain.
Now, forget molecules for a second. When you hug someone 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 and turn 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 the narcotics or opioids like morphine. Narcotics mainly by activating mu opioid receptors.
footnote
But if so, can narcotics also treat pain of separation? It was Jaak Panksepp who found the answer. Panksepp gave his puppies in a experiment tiny, tiny doses of morphine, lower than the lowest doses that are used to treat physical pain, his puppies immediately stopped crying and started playing with other as if they no longer miss their mothers.
Let’s go to humans now. When mental in humans becomes too intense to bear people, some people, do anything to stop it, even try to kill themselves. Indeed, and I’m saying this a clinical psychiatrist, unbearable mental pain is a huge risk factor for suicide.
footnote
But if treat physical pain, and if they can soothe the mental pain separation, can they also help suicidal people become less suicidal? few 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, called buprenorphine, for four weeks.
We that tiny, tiny doses of buprenorphine, which are too low to treat physical pain, helped many them become less suicidal. But narcotics are extremely dangerous drugs. They may cause addiction, and they’re lethal in overdose. In contrast, endorphins 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 mu opioid receptors in a way that resembles how activate them, we might be able to treat physical and mental pain without of the dangerous side effects of narcotics. And when my research team came this conclusion, I suddenly remembered what I had learned in Kandel’s lab many, many 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 happens when they’re activated by just one drug. So our research team then used molecular computing technologies to create a detailed virtual model of the human mu opioid receptor. then, with the help of programs known as molecular docking algorithms, we screened thousands existing drugs on a virtual model of the receptor.
Eventually, found a way to teach an old dog, that’s human mu opioid receptor, some new tricks. We found 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 to run many tests and clinical trials before we can be certain that combination does exactly what we think it does. But both of these drugs have around for many, many years, and they’ve been used by millions of people. So we 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 of mourning and depression sadness. And when it gets severe enough, it can actually make people suicidal. Endorphins are brain’s natural remedy physical and mental pain, and they work mainly, not exclusively, but mainly by activating opioid receptors.
Now, narcotics also activate mu opioid receptors, but in a way that causes addiction and can to death. And this is why narcotics are so dangerous. New computational technologies have helped us identify two existing drugs that 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 thing I’m going to say, regardless of drugs, you have the ability to family and friends who are in severe physical or mental pain.
Thank you very much.
(Applause)
Footnotes
note
“Panksepp his puppies, in a separation experiment, tiny, tiny doses morphine – lower than the lowest doses that are used to treat physical pain. And his puppies 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 quite alert and moved about normally while isolated from their mothers.
note
“Unbearable pain is a huge risk factor for suicide.”
For information about why mental pain is a significant risk factor for suicide, see here.
note
“A few years ago, with Panksepp and other colleagues, my research team conducted clinical trial. We gave people who were severely suicidal, very low doses of a narcotic drug, buprenorphine car buprenorphine four weeks. We discovered that tiny, tiny doses of buprenorphine, which are low to treat physical pain, help many of them become suicidal.”
For more information about these study results, see here.
note
“Some GPCRs be activated 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 more information how GPCRs may be activated by two different drugs at the same time, see here.