I’m Yoram Youvel. I’m a psychiatrist and neuroscientist the Hebrew University of Jerusalem. And when I was 14 old, my father died. I was sitting in class when my mother and my grandfather knocked on 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 crushing pain my chest. I can still feel a glimpse of it I 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 broke my heart.
Do you remember the pain you felt when someone your heart? When your best friend or your mother died? Or 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 between physical mental pain? And most importantly, how can we make mental pain better? with many scientists and physicians, I spent years searching for to these questions.
Now, growing up, I never heard the words, “We want you to be a doctor and brain scientist like your father.” But somehow that’s what happened. Twelve years after my father died, I was a graduate at 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 protein that’s part of a synapse. And synapses are structures through which nerve cells communicate each other. Now 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 is doing here.
And when I that, I didn’t really realize that work on that receptor, which seemed completely unrelated to my future work as clinical psychiatrist, would one day help us in our search for better treatments for physical and mental pain.
Now big step along that way was the work of Panksepp, my other great scientific mentor. In a classical experiment, Panksepp separated puppies from their mothers for 15 minutes. more than that because he loved animals. When puppies lose their mothers, make a sound which is called the separation distress cry. it goes like this.
(Imitates puppy wailing)
Puppies do it, do it, babies do it. All young mammals do it when they’re in pain or when miss their mothers. And we all know how this cry makes us feel inside.
Panksepp and colleagues then traced the brain circuits that produce these cries in guinea pigs, they made a startling discovery. That these are the very same circuits that are active humans feel sad and when 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 an alarm system. Its task is to prevent damage. When babies their mothers, they hurt and they cry. Which brings their mothers back, and also makes them seek their mothers. In the wild, this is life-saving. Puppies and babies cannot survive without their mothers.
So now we know why we mental pain. It is the glue that keeps us together in couples, in families and communities. And when someone love goes away or is taken away from us, it’s this which draws us back together. And once we realize this, then can answer an age-old question that poets and philosophers have been asking for thousands of years.
Does love hurt? What do you think? Does love always hurt? Yes, love always hurts, course. Because that’s what it’s supposed to do. Mental pain is simply the high price, the high price, that we 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 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 in the brain during aerobic exercise or when we’re close to someone we love, and immediately after severe injuries.
And 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 receptor I worked on in Kandel’s lab, mu opioid receptors are GPCR.
Here’s how they work. Like all GPCRs, opioid receptors are made of seven spirals or loops that are stacked together, sticking through sides of the cell membrane. Like this, OK.
And endorphins attach to mu opioid receptors from the outside, they cause to change their shape. Like this, OK? And this triggers a series of events inside the neurons which eventually ease the pain.
Now, forget the for a second. When you hug someone you love who is suffering from severe physical or pain, you actually cause her brain to release endorphins. They attach to mu receptors in her synapses and turn them on, and they her pain.
And yet, sometimes mental pain gets so intense that 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 mainly by activating mu opioid receptors.
footnote
But if so, can narcotics also treat the pain of separation? 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 physical pain, and his puppies immediately stopped crying and started playing with each other as if they no longer miss their mothers.
Let’s to humans now. When mental pain in humans becomes too intense to bear people, some people, will 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 for suicide.
footnote
But if narcotics treat physical pain, and if they can soothe mental pain of separation, can 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 narcotic drug, called buprenorphine, for four weeks.
We discovered that tiny, tiny doses of buprenorphine, which are too low to treat physical pain, helped many of become less suicidal. But narcotics are extremely dangerous drugs. may cause addiction, and they’re lethal in overdose. In contrast, endorphins are not lethal overdose, and they’re much less likely to cause addiction. So narcotics and endorphins activate mu opioid receptors in different ways.
Now, if could find drugs that activate mu opioid receptors in way that resembles how endorphins activate them, we might able to treat physical and mental pain without some the dangerous side effects of narcotics. And when my research team came to conclusion, I suddenly remembered what I had learned in Kandel’s lab many, many years ago.
footnote
Some GPCRs can be activated two different drugs at the same time. And when this happens, the result be different from what happens when they’re activated by just one drug. So our team then used molecular computing technologies to create a virtual model of the human mu opioid receptor. And then, with the help of programs known as molecular docking algorithms, we screened thousands of existing drugs on a virtual model of the receptor.
Eventually, we found way to teach an old dog, that’s the human mu opioid receptor, some new tricks. We found two drugs are not narcotics, and they work together in very, very small doses to activate the human mu receptor.
I’m not telling you their names, because we still have to run many and clinical trials before we can be certain that their combination exactly what we think it does. But both of drugs have been around for many, many years, and they’ve been used by millions of people. So we know they’re safe for humans.
Here’s our bottom line. Let’s what we’ve seen. First and foremost, mental pain is real. It’s hardwired into our brains. And mental pain an essential part of mourning and depression and sadness. And when it gets severe enough, it can actually make people suicidal. Endorphins are brain’s natural remedy for physical mental pain, and they work mainly, not exclusively, but mainly by activating mu opioid receptors.
Now, narcotics activate mu opioid receptors, but in a way that causes addiction and lead to death. And this is why narcotics are so dangerous. New technologies have helped us identify two existing drugs that together may treat physical and pain without some of the severe side effects of narcotics. However, this is still a work in progress. would be a few years before it may become an approved treatment.
But, and this the last thing I’m going to say, regardless of drugs, you have the ability to family and friends who are in severe physical or pain.
Thank you very much.
(Applause)
Footnotes
note
“Panksepp gave his puppies, a separation experiment, tiny, tiny doses of morphine – lower than 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 their 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 a huge risk factor for suicide.”
For more information about mental pain is a significant risk factor for suicide, here.
note
“A few years ago, together with and other colleagues, my research team conducted a clinical trial. We gave people were severely suicidal, very low doses of a narcotic drug, car buprenorphine for four weeks. We discovered that tiny, tiny doses of buprenorphine, which are too low to treat pain, help many of them become less suicidal.”
For more information about these study results, see here.
note
“Some GPCRs can be by two different drugs at the same time. And this happens, the result may be different for what when they’re activated by just one drug.”
For more information how GPCRs may be activated by two different drugs the same time, see here.