I’m Yoram Youvel. I’m a psychiatrist and at the Hebrew University of Jerusalem. And when I was 14 years old, my father died. I was sitting in when my mother and my grandfather knocked on the door and asked me out the corridor.
“Your father’s very sick,” my mother said. “Your father is dead.” And then I 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 a young, strong, happy, healthy man. He was my hero. And his death broke 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 that he doesn’t love you anymore. You probably do.
But why do we feel mental pain at all? what’s the relationship between physical and mental pain? And most importantly, how can we make mental pain better? Together with 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.” But that’s what happened. Twelve years after my father died, I was a graduate student Dr. Eric Kandel’s lab at Columbia University. Eric, who won the Nobel Prize for his work on 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. Now that receptor a GPCR. That’s a G protein coupled receptor. I’ll explain this means in a minute and then you’ll understand what this stack of markers is here.
And when I did that, I didn’t really realize that work on receptor, which seemed completely unrelated to my future work as clinical psychiatrist, would one day help us in our search better treatments for physical and mental pain.
Now a big step along that way was the work of Jaak Panksepp, other great scientific mentor. In a classical experiment, Panksepp separated puppies from their mothers 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 goes like this.
(Imitates puppy wailing)
Puppies do it, kittens do it, babies do it. young mammals do it when they’re in pain or when miss their mothers. And we all know how this cry makes us inside.
Panksepp and his colleagues then traced the brain circuits that produce cries in guinea pigs, and they made a startling discovery. That these are the very same that are active when humans feel sad and when they experience depression. And these circuits also part of the brain’s pain matrix that mediates our of physical and mental pain.
But why are we born with this terrible gift hardwired our brains? Well, probably because like any pain, mental pain is an alarm system. Its task is to 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, is life-saving. Puppies and babies cannot survive without their mothers.
So now we know why have mental pain. It is the glue that keeps us together couples, in families and communities. And 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, we can answer an age-old question that poets and philosophers have been asking 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 to do. Mental pain is simply the high price, very high price, that we pay for our ability 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 not entirely defenseless against pain our brains produce endorphins or endogenous opioids, our very own feel-good molecules, the natural remedy for both physical 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 most important among them are mu opioid receptors. just like the receptor I worked on in Kandel’s lab, 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 both of the cell membrane. Like this, OK.
And when endorphins attach to mu opioid receptors from the outside, they cause to change their shape. Like this, OK? And this triggers series of events inside the neurons which eventually ease 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 mu 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 drugs that can ease any physical pain. These are the 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 his puppies in a separation experiment tiny, tiny doses morphine, lower than the lowest doses that are used to treat pain, and his puppies immediately stopped crying and started playing with each other as if no longer miss their mothers.
Let’s go to humans now. When mental pain 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 as clinical psychiatrist, unbearable mental pain is a huge risk factor for suicide.
footnote
But if narcotics treat physical pain, and if they soothe the mental pain of separation, can they also suicidal people become less suicidal? A few years ago, together with Panksepp other colleagues, my research team conducted a clinical trial. We gave who were severely suicidal very low doses of a narcotic drug, buprenorphine, for four weeks.
We discovered that tiny, tiny doses of buprenorphine, are too low to treat physical pain, helped many of them become less suicidal. But are extremely dangerous 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. narcotics and 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 endorphins activate them, we might be able to treat physical and mental pain without some of dangerous side effects of narcotics. And when my research team came to this conclusion, I suddenly remembered what I learned in 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 be different from what happens when they’re activated by one drug. So our research team then used molecular computing technologies to create a detailed virtual model of human mu opioid receptor. And then, with the help of known as molecular docking algorithms, we screened thousands of existing drugs 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. found two drugs that 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 we still to run many tests and clinical trials before we be certain that their combination does exactly what we think it does. But both of these drugs have been around for many, many years, and they’ve been used by millions people. So we know that 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 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 mental pain, they work mainly, not exclusively, but mainly by activating mu opioid receptors.
Now, also activate mu opioid receptors, but in a way that causes and can lead to death. And 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 side effects of narcotics. However, this is still work in progress. It would be a few years it may become an approved treatment.
But, and this is the last I’m going to say, regardless of drugs, you have the ability to help family and 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 morphine – lower than the lowest doses that are to treat physical pain. And his puppies immediately stopped crying and started playing each other as if they no longer miss their mothers.”
According to from this 1978 study, morphine-treated puppies were quite alert and about normally while isolated from their mothers.
note
“Unbearable mental pain is a 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 who severely suicidal, very low doses of a narcotic drug, buprenorphine car 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 by two different drugs at the same time. And when this happens, the result may be different for happens when they’re activated by just one drug.”
For information about how GPCRs may be activated by two different drugs at the time, see here.