I’m Youvel. I’m a psychiatrist and neuroscientist at the Hebrew University of Jerusalem. And when I was 14 years old, my father died. I was sitting in class when mother and my grandfather knocked on the door and asked out to the corridor.
“Your father’s very sick,” my mother said. “Your father dead.” And then I felt it. A crushing pain in my chest. I can still a glimpse of it whenever I think of my father.
He was doctor, a scientist, a 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 or your mother died? Or the man you loved told that he doesn’t love you anymore. You probably do.
But why we feel mental pain at all? And what’s the relationship between physical and mental pain? And most importantly, how 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 words, “We want you to be a doctor and a 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 for his work on the molecular basis of memory, was the mentor. Passionate, energetic and inspiring.
Under his guidance, I studied 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 receptor. I’ll explain what this means in a minute and then you’ll what this stack of markers is doing here.
And when I did that, I didn’t really realize that work on that receptor, which seemed completely unrelated to my future work as a clinical psychiatrist, would one day help us our search for better treatments for physical and mental pain.
Now a big step along that way was the work 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 the separation distress cry. And it goes like this.
(Imitates puppy wailing)
Puppies do it, do it, babies do it. All young mammals do it when they’re in or when they miss their mothers. And we all know how this cry makes us feel inside.
Panksepp and his colleagues then traced brain circuits that produce these cries in guinea pigs, and they made a startling discovery. That these are the very same circuits that are active when humans feel sad and when they depression. And these circuits are also part of the brain’s matrix that mediates our sensations of physical and mental pain.
But why are we born 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. 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 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 someone we love goes away or is taken away us, it’s this 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 asking for of years.
Does love always hurt? What do you think? love always hurt? Yes, love always hurts, of course. Because that’s what it’s supposed do. Mental pain is simply the high price, the very high price, that we pay for our ability to love. And personally, and, you know, I’ve been around the a couple of times, personally, I think it’s worth it.
But we’re not entirely defenseless against because our brains produce endorphins or endogenous opioids, our very feel-good molecules, the natural remedy for both physical and pain. Endorphins are released in the brain during aerobic exercise or when we’re close to someone we love, 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 opioid receptors. And just like the receptor I worked on in Kandel’s lab, mu receptors are GPCR.
Here’s how they work. Like all GPCRs, mu opioid receptors are made of spirals or loops that are stacked together, sticking through both sides the cell membrane. Like this, OK.
And when endorphins attach to mu opioid receptors from the outside, they them to change their shape. Like this, OK? And triggers a series of events inside the neurons which eventually ease the pain.
Now, forget the molecules for a second. When hug someone you love who is suffering from severe physical or mental pain, you actually cause her brain to release endorphins. They to mu opioid receptors in her synapses and turn on, and they soothe her pain.
And yet, sometimes mental pain gets so intense that amount of love can soothe it. But medicine has powerful drugs that can any physical pain. These are the narcotics or opioids like morphine. Narcotics work mainly activating mu opioid receptors.
footnote
But if so, can narcotics also treat pain of separation? It was Jaak Panksepp who found the answer. Panksepp gave his puppies in separation 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 with each other as if they no longer miss their mothers.
Let’s to humans now. When mental pain in humans becomes too intense bear people, some people, will do anything to stop it, even try 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 if they can soothe the mental of separation, can they also help suicidal people become less suicidal? A few years ago, together Panksepp and other colleagues, my research 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 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 lethal overdose, and they’re much less likely to cause addiction. So narcotics and endorphins 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 to treat physical and mental pain without some of the dangerous side effects of narcotics. And when research team came to this conclusion, I suddenly remembered what I had in Kandel’s lab many, many years ago.
footnote
Some can be activated by two different drugs at the same time. And when happens, the result may be different from what happens when they’re activated by just one drug. our research team then used molecular computing technologies to create a detailed virtual model of the human mu opioid receptor. And then, with the help of programs known as molecular algorithms, we screened thousands of existing drugs on a virtual model of the receptor.
Eventually, we found a way to teach an old dog, that’s the mu opioid receptor, some new tricks. We found two drugs 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 still have to run many tests and clinical trials before we can be certain that their does exactly what we think it does. But both of these drugs have around for many, many years, and they’ve been used by millions of people. So we know that 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. mental pain is an essential part of mourning and depression and sadness. And when gets severe enough, it can actually make people suicidal. Endorphins are brain’s natural remedy for physical and mental pain, and they work mainly, not exclusively, but mainly by activating mu receptors.
Now, narcotics also activate mu opioid receptors, but in way that causes addiction and can lead to death. And this is why 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 effects of narcotics. However, this is still a work in progress. It would be a few years before it may become an approved treatment.
But, and is the last thing I’m going to say, regardless of drugs, you have the to help family and friends who are in severe or mental pain.
Thank you very much.
(Applause)
Footnotes
note
“Panksepp gave his puppies, in a separation experiment, tiny, tiny of morphine – lower than the 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 their mothers.”
According to results from this 1978 study, morphine-treated puppies were quite alert moved about normally while isolated from their mothers.
note
“Unbearable mental pain is a risk factor for suicide.”
For more information about why mental is a significant risk factor for suicide, see here.
note
“A few ago, together with Panksepp and other colleagues, my research team conducted a clinical trial. We gave people who were severely suicidal, very doses of a narcotic drug, buprenorphine car buprenorphine for four weeks. We discovered that tiny, tiny doses of buprenorphine, which are too low treat physical pain, help many of them become less suicidal.”
For information about these study results, see here.
note
“Some GPCRs can be activated two different drugs at the same time. And when this happens, the result may be different for what when they’re activated by just one drug.”
For more information about GPCRs may be activated by two different drugs at the same time, see here.