I’m Yoram Youvel. I’m a psychiatrist and neuroscientist the Hebrew University of Jerusalem. And when I was 14 years old, my father died. I was sitting in class my mother and my grandfather knocked on the door and asked me to the corridor.
“Your father’s very sick,” my mother said. “Your father is dead.” And I felt it. A crushing pain in my chest. I can still feel a glimpse of whenever I think of my father.
He was a doctor, 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 you felt when someone broke 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 at all? And what’s the relationship between physical and mental pain? And most importantly, how can we make mental pain better? with many scientists and physicians, I spent years searching answers to these questions.
Now, growing up, I never heard the words, “We want you to be a doctor and a brain scientist like your father.” But somehow that’s what happened. years after my father died, I was a graduate student at Dr. Eric Kandel’s lab at University. Eric, who won the Nobel Prize for his work on the molecular basis 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 through which nerve cells communicate with each other. Now 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 did that, I didn’t really realize that work on that receptor, seemed completely unrelated to my future work as a clinical psychiatrist, one day help us in our search for better 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. more than that because he loved animals. When puppies lose their mothers, they make a sound which is the separation distress cry. And it goes like this.
(Imitates puppy wailing)
Puppies do it, kittens do it, do it. All young mammals do it when they’re in or when they miss their mothers. And we all know how cry makes us feel inside.
Panksepp and his colleagues then traced the brain that produce these cries in guinea pigs, and they made a startling discovery. these are the very same circuits that are active when humans 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 born with this terrible gift hardwired into our brains? Well, because like any pain, mental pain is an alarm system. Its is to prevent damage. When babies lose their mothers, they hurt and they cry. Which brings their mothers back, and it also them seek their mothers. In the wild, this is life-saving. Puppies and babies survive without their mothers.
So now we know why we have mental pain. It is the glue 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 can answer an age-old question that 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 is simply the high price, the very high price, that we pay for our ability to love. And personally, and, you know, I’ve around the block a couple of times, personally, I think it’s worth it.
But we’re not entirely defenseless 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 someone we love, and immediately after severe injuries.
And we now know what endorphins do, they attach special receptors in the brain, and the most important them are mu opioid receptors. And just like the receptor I on in Kandel’s lab, mu opioid receptors are GPCR.
Here’s they work. Like all GPCRs, mu opioid receptors are made of spirals or loops that are stacked together, sticking through both sides of the membrane. Like this, OK.
And when endorphins attach to mu opioid receptors from outside, they cause them to change their shape. Like this, OK? this triggers a series of events inside the neurons which eventually ease the pain.
Now, forget the molecules for a second. When you someone you love who is suffering from severe physical or mental pain, you actually cause her brain to release endorphins. They attach to mu receptors in her synapses and turn them on, and they soothe her pain.
And yet, sometimes pain gets so 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 by activating mu opioid receptors.
footnote
But if so, narcotics also treat the pain of separation? It was Jaak who found the answer. Panksepp gave his puppies in a separation tiny, tiny doses of morphine, lower than the lowest that are used to treat physical pain, and his puppies immediately stopped and started playing with each other as if they no longer miss their mothers.
Let’s go to humans now. When mental pain humans becomes too intense to bear people, some people, will do anything to stop it, even try to kill themselves. Indeed, I’m saying this as a clinical psychiatrist, unbearable mental 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 help suicidal people become less suicidal? 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, for four weeks.
We discovered that tiny, tiny doses of buprenorphine, which 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. 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 find drugs that activate mu opioid in a way that resembles how endorphins activate them, we might able to treat physical and mental pain without some of the side effects of narcotics. And when my research team to this conclusion, I suddenly remembered what I had learned in Kandel’s lab many, years ago.
footnote
Some GPCRs can be activated by two drugs at the same time. And when this happens, the may be different from what happens when they’re activated by just one drug. So our research then used molecular computing technologies to create a detailed model of the human mu opioid receptor. And then, with help of programs known as molecular docking algorithms, we screened thousands of existing drugs on virtual model of the receptor.
Eventually, we found a 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, small doses to activate the human mu opioid receptor.
I’m not telling you their names, because we still have to run many tests and clinical before we can be certain that their combination does exactly what we think it does. both of these drugs have been around for many, many years, 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. 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, and they work mainly, exclusively, but mainly by activating mu opioid receptors.
Now, narcotics also activate mu opioid receptors, but in a that 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 some of severe side effects of narcotics. However, this is still a in progress. It would be a few years before it may become an approved treatment.
But, and this is the last thing I’m going to say, regardless of drugs, you have the ability help family and friends who are in severe physical or mental pain.
Thank very much.
(Applause)
Footnotes
note
“Panksepp gave his puppies, in a separation experiment, tiny, tiny doses of – lower than the lowest doses that are used to treat physical pain. And his puppies immediately crying and started playing with each other as if no longer miss their mothers.”
According to results from 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 pain is a significant risk factor for suicide, see here.
note
“A few years ago, together with Panksepp and other colleagues, my research team conducted a clinical trial. gave people who were severely suicidal, very low doses of a narcotic drug, buprenorphine car buprenorphine for four weeks. discovered that tiny, tiny doses of buprenorphine, which are too to treat physical pain, help many of them become less suicidal.”
For information about these study results, see here.
note
“Some GPCRs can be activated by two different drugs at the same time. And when this happens, the result may different for what happens when they’re activated by just one drug.”
For more information about how GPCRs be activated by two different drugs at the same time, see here.