I’m Yoram Youvel. I’m psychiatrist and neuroscientist at the Hebrew University of Jerusalem. when I was 14 years old, my father died. was sitting in class when my mother and my grandfather knocked on the and asked me out to the corridor.
“Your father’s very sick,” my said. “Your father is dead.” And then I felt it. A crushing pain my chest. I can still feel a glimpse of it whenever I think of my father.
He was a doctor, a scientist, paratrooper. He was a young, strong, happy, healthy man. He was my hero. And his death broke my heart.
Do remember the pain you felt when someone broke your heart? When your best friend or your died? Or the man you loved told you that he doesn’t love you anymore. You probably do.
But why do we feel pain at all? And what’s the relationship between physical and mental pain? most importantly, how can we make mental pain better? Together with scientists and physicians, I spent years searching for answers to questions.
Now, growing up, I never heard the words, “We want to be a doctor and a brain scientist like your father.” But somehow that’s happened. Twelve years after my father died, I was a student at Dr. Eric 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 a receptor. It’s a 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 protein coupled receptor. I’ll explain this means in a minute and then you’ll understand what this stack 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 search for treatments for physical and mental pain.
Now a big step along that way was the of Jaak Panksepp, my other great scientific mentor. In a classical experiment, separated puppies from their mothers for 15 minutes. Never more than that because loved animals. When puppies lose their mothers, they make a sound which is called the separation distress cry. And it goes like this.
(Imitates puppy wailing)
Puppies do it, do it, babies do it. All young mammals do when they’re in pain or when they miss their mothers. And we all know this cry makes us feel inside.
Panksepp and his then traced the brain circuits that produce these cries in guinea pigs, and they made startling discovery. That these are the very same circuits are active when humans feel sad and when they experience depression. And these circuits are also part of the brain’s pain matrix that our sensations of 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 an alarm system. Its task is to prevent damage. When babies lose their mothers, they and they cry. Which brings their mothers back, and also makes them seek their mothers. In the wild, this is life-saving. and babies cannot survive without their mothers.
So now we know why we have mental pain. It is the 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 answer an age-old question that poets and philosophers have been for thousands of years.
Does love always hurt? What do 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 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, think it’s worth it.
But we’re not entirely defenseless against pain because our produce endorphins 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 immediately after severe injuries.
And we now know what endorphins do, they attach to special receptors 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, opioid receptors are made of seven spirals or loops that stacked together, sticking through both sides of the cell membrane. Like this, OK.
And when endorphins attach mu opioid receptors from the outside, they cause them change their shape. Like this, OK? And this triggers series of 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 her brain to release endorphins. They attach to mu opioid 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 any physical pain. are the narcotics or opioids like morphine. Narcotics work mainly by mu opioid receptors.
footnote
But if so, can narcotics also treat the pain 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 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, will do 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 of separation, can they also suicidal people become less suicidal? A few years ago, together with Panksepp and other colleagues, my research team a clinical trial. We gave people who were severely 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 of them become less suicidal. narcotics are extremely dangerous drugs. They 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 probably activate mu opioid receptors different ways.
Now, if we could find drugs that activate mu opioid receptors in a way that how endorphins activate them, we might be able to treat physical and mental pain without some of the side effects of narcotics. And when my research team came to this conclusion, I suddenly remembered what I had in Kandel’s lab many, many years ago.
footnote
Some GPCRs be activated by two different drugs at the same time. And when this happens, the result may be different from what happens when they’re activated by just one drug. So research team then used molecular computing technologies to create a detailed virtual model the human mu opioid receptor. And then, with the of programs known as molecular docking algorithms, we screened thousands of drugs on a virtual model of the receptor.
Eventually, we found a to teach an old dog, that’s the human mu opioid receptor, some new tricks. We two 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, because we still have to many tests and clinical trials before we can be certain their combination does exactly what we think it does. But both 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 humans.
Here’s our 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 severe enough, it can actually make people suicidal. Endorphins are brain’s natural remedy for and mental pain, and they work mainly, not exclusively, mainly by activating mu 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 have helped us identify two existing 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, and this is the last thing I’m to say, regardless of drugs, you have the ability to help family and friends who are in severe physical or mental pain.
Thank you much.
(Applause)
Footnotes
note
“Panksepp gave his puppies, 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 playing each other as if they no longer miss their mothers.”
According to from this 1978 study, morphine-treated puppies were quite alert and moved about normally while isolated from mothers.
note
“Unbearable mental pain is a huge risk factor for suicide.”
For more information about why mental pain is a significant risk factor for suicide, see here.
note
“A years ago, together with Panksepp and other colleagues, my research team conducted a trial. We gave people who were severely suicidal, very low doses of a narcotic drug, car buprenorphine for four weeks. We discovered that tiny, tiny doses of buprenorphine, are too low to treat physical pain, help many of them become less suicidal.”
For more information these study results, see here.
note
“Some GPCRs can be activated by two different drugs the same time. And when this happens, the result may be different for what happens they’re activated by just one drug.”
For more information about how GPCRs may activated by two different drugs at the same time, here.