I’m Yoram Youvel. I’m a psychiatrist and neuroscientist at the University of Jerusalem. And when I was 14 years old, my father died. I sitting in class when my mother and my grandfather knocked the door 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 feel a glimpse 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 heart.
Do you remember the pain you felt when someone broke your heart? When your best friend or your mother died? Or the man you loved you that he doesn’t love you anymore. You probably do.
But 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? Together with many scientists and physicians, I spent years searching 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 my father died, I was graduate student at Dr. Eric Kandel’s lab at Columbia University. Eric, who won Nobel Prize for his work on the molecular basis of memory, was ultimate mentor. Passionate, energetic and inspiring.
Under his guidance, studied a 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 minute and you’ll understand what this stack of markers is doing here.
And when I did that, I didn’t really realize that on that receptor, which seemed completely unrelated to my future work 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 the work of Jaak Panksepp, my other great scientific mentor. In classical experiment, Panksepp separated puppies from their mothers for 15 minutes. Never more than that because he loved animals. When puppies lose their mothers, they make sound which is called the separation distress cry. And goes like this.
(Imitates puppy wailing)
Puppies do it, kittens do it, babies do it. All young do it when they’re in pain or when they their mothers. And we all know how this cry makes us feel inside.
Panksepp and his colleagues then traced the brain circuits produce these cries in guinea pigs, and they made a startling discovery. That these are the same circuits that are active when humans feel sad and when they experience depression. And circuits are also part of the brain’s pain matrix that mediates sensations of physical and mental pain.
But why are we born with this terrible gift hardwired into our brains? Well, probably because like pain, mental pain is an alarm system. Its task is prevent damage. When babies lose their mothers, they hurt and they cry. Which brings their mothers back, and also makes them seek their mothers. In the wild, is life-saving. Puppies and babies cannot survive without their mothers.
So now know why we have mental pain. It is the that keeps us together in couples, in families and communities. And when we love goes away or is taken away from us, it’s this pain 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 years.
Does love always hurt? What do you think? Does love hurt? Yes, love always hurts, of course. Because that’s what it’s to do. Mental pain is simply the high price, the very high price, that we pay for our ability to love. 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 because our brains produce endorphins or endogenous opioids, our very own feel-good molecules, the natural remedy for physical and mental pain. Endorphins are released in the 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 receptors. And just like the receptor I worked on 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 to mu receptors from the outside, they cause them to change their shape. Like this, OK? And this triggers a series of 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 mental pain, you actually cause brain to release endorphins. They attach to mu opioid in her synapses and turn them on, and they soothe her pain.
And yet, sometimes mental pain gets intense that no amount of love can soothe it. But medicine powerful drugs that can ease any physical pain. These are the narcotics or opioids like morphine. Narcotics work mainly by activating opioid receptors.
footnote
But if so, can narcotics treat the pain of separation? It was Jaak Panksepp found the answer. Panksepp gave his puppies in a separation experiment tiny, doses of morphine, lower than the lowest doses that used to treat physical pain, and his puppies immediately stopped crying and started playing with each other as they no longer miss their mothers.
Let’s go to 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, and I’m saying this as a clinical psychiatrist, unbearable mental is a huge risk factor for suicide.
footnote
But if narcotics treat physical pain, and they can soothe the mental pain of separation, can they 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 of a narcotic drug, called buprenorphine, for four weeks.
We discovered that tiny, tiny doses of buprenorphine, which are too low to treat pain, helped many of them become less suicidal. But narcotics are extremely dangerous drugs. They may cause addiction, they’re lethal in overdose. In contrast, endorphins are not in overdose, and they’re much less likely to cause addiction. So narcotics and endorphins probably activate mu opioid receptors in different ways.
Now, if we could drugs that activate mu opioid receptors in a way that resembles how endorphins activate them, might be able to treat physical and mental pain without some of the dangerous effects of narcotics. And when my research team came to this conclusion, I suddenly remembered what I had learned 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 by just one drug. So our research team then molecular computing technologies to create a detailed virtual model of the human mu opioid receptor. And then, the help of programs known as molecular docking algorithms, we screened thousands existing drugs on a virtual model of the receptor.
Eventually, we found a way to teach an dog, that’s the human mu opioid receptor, some new tricks. We found drugs that are not narcotics, and they work together in very, small doses to activate the human mu opioid receptor.
I’m not telling you their names, because we still have run many tests and clinical trials before we can be certain that their combination does exactly what we think does. But both of these drugs have been around for many, many years, they’ve been 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 into our brains. And mental pain is an essential part mourning and depression and sadness. And when it gets severe enough, it can actually make people suicidal. Endorphins are brain’s remedy for physical and mental pain, and they work mainly, not exclusively, but mainly by mu opioid receptors.
Now, narcotics also activate mu opioid receptors, but in a way causes addiction and can lead to death. And this is why are so dangerous. New computational technologies have helped us identify two existing drugs that together may treat physical and mental pain without of the severe side effects of narcotics. However, this is still a work in progress. It would be few years before it may become an approved treatment.
But, and this is 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 very much.
(Applause)
Footnotes
note
“Panksepp gave his puppies, in a 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 as if they no longer miss their mothers.”
According to results from this 1978 study, morphine-treated puppies were quite alert and moved about normally while isolated from their mothers.
note
“Unbearable mental pain a huge risk factor for suicide.”
For more information about why mental pain is a significant risk factor for suicide, see here.
note
“A few years ago, together with Panksepp other 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. discovered that tiny, tiny doses of buprenorphine, which are low to treat physical pain, help many of them become less suicidal.”
For more information about these study results, see here.
note
“Some GPCRs can be activated by different drugs at the same time. And when this happens, the result may be different for what happens when they’re activated by just drug.”
For more information about how GPCRs may be activated by two different drugs at the same time, here.