I’m Youvel. I’m a psychiatrist and neuroscientist at the Hebrew University of Jerusalem. when I was 14 years old, my father died. I was sitting in class when my mother and my knocked on the door and asked me out to the corridor.
“Your father’s very sick,” my mother said. “Your is dead.” And then I felt it. A crushing pain in my chest. I can still feel glimpse of it whenever 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 remember the pain you felt when someone broke your heart? When your best friend or mother died? Or the man you loved told you that doesn’t love you anymore. You probably do.
But why we feel mental pain at all? And what’s the relationship between and mental pain? And most importantly, how can we make mental pain better? Together with many scientists and physicians, I years searching for 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 a student at Dr. Eric Kandel’s lab at Columbia University. Eric, who won the Nobel Prize for his work on the 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 are structures 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 then you’ll understand what this stack of markers is doing here.
And when I did that, I didn’t really realize work on that receptor, which seemed completely unrelated to my future work as a clinical psychiatrist, would day help us in our search for better treatments for physical and mental pain.
Now a big step along that way was work of Jaak Panksepp, my other great scientific mentor. In a classical experiment, separated puppies from their mothers for 15 minutes. Never more that because he loved animals. When puppies lose their mothers, make a sound which is called the separation distress cry. And it goes this.
(Imitates puppy wailing)
Puppies do it, kittens do it, babies it. All young mammals do it when they’re in pain when they miss their mothers. And we all know how this cry makes feel inside.
Panksepp and his colleagues then traced the brain circuits that produce these cries in guinea pigs, and they made a startling discovery. That these are the very same that are active when humans feel sad and when they experience depression. And these circuits are part of the brain’s pain matrix that mediates our of physical and mental pain.
But why are we born with this terrible gift hardwired our brains? Well, probably because like any pain, mental pain 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 makes them seek their mothers. In 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 couples, in families and communities. And when someone we love away or is taken away from us, it’s this pain which draws us back together. And once we realize this, 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? Does love always hurt? Yes, love 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 our ability to love. And personally, and, you know, I’ve been around block a couple of times, personally, I think it’s worth it.
But we’re not entirely defenseless against pain our brains produce endorphins or endogenous opioids, our very own feel-good molecules, the natural remedy for both and mental pain. Endorphins are released in the brain during aerobic exercise when we’re close to someone we love, and immediately after severe injuries.
And we now know what do, they attach to special receptors in the brain, and the most important among are mu opioid receptors. And just like the receptor I worked 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 both of the cell membrane. Like this, OK.
And when endorphins attach to mu opioid receptors from the outside, they cause to change their shape. Like this, OK? And this triggers a series 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 mental pain, you actually cause her to release endorphins. They attach to mu opioid receptors in her synapses and turn them on, they soothe her pain.
And yet, sometimes mental pain gets so intense that no amount of love can soothe it. But medicine has powerful 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 also the pain of separation? It was Jaak Panksepp who found the answer. Panksepp gave his puppies in a separation experiment tiny, tiny doses of morphine, lower than lowest doses that are used to treat physical pain, and his puppies immediately stopped crying and started playing with each as if they no longer miss their mothers.
Let’s go to humans now. When mental pain in humans becomes too intense to people, some people, will do anything to stop it, even to kill themselves. Indeed, and I’m saying this as a clinical psychiatrist, unbearable mental pain is a risk factor for suicide.
footnote
But if narcotics treat pain, and if they can soothe the mental pain of separation, they also help suicidal people become less suicidal? A years ago, together with Panksepp and other colleagues, my research team conducted a clinical trial. We gave people who severely suicidal very low doses of a narcotic drug, buprenorphine, for four weeks.
We discovered that tiny, tiny doses of buprenorphine, which are low to treat physical pain, helped many of them become less suicidal. But narcotics are extremely dangerous drugs. may cause addiction, and they’re lethal in overdose. In contrast, endorphins are not lethal in overdose, and they’re much less likely to cause addiction. So narcotics and endorphins probably activate mu opioid receptors in different ways.
Now, we could find drugs that activate mu opioid receptors in a that resembles how endorphins activate them, we might be able to treat physical and mental pain without some of dangerous side effects of narcotics. And when my research team came to this conclusion, I suddenly remembered what had learned in Kandel’s lab many, many years ago.
footnote
GPCRs can be activated by two different drugs at the same time. And when this happens, the 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 opioid receptor. And then, with the 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. We found two 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 and clinical trials before we can be certain that their combination does exactly what we think it does. But both these drugs have been around for many, many years, they’ve been used by millions of people. So we know that they’re for humans.
Here’s our bottom line. Let’s summarize what we’ve seen. First foremost, mental pain is real. It’s hardwired into our brains. And mental pain is an essential part of mourning and depression and sadness. when it gets severe enough, it can actually make 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 a way that causes addiction and can lead to death. And this is why narcotics are so dangerous. computational technologies have helped us identify two existing drugs together may treat physical and mental pain without some of the side effects of narcotics. However, this is still a work in progress. It would be a few years before it become an approved treatment.
But, and this is the last thing I’m going to say, regardless of drugs, you have the to help family and friends who are in severe physical 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 treat physical pain. And his puppies immediately stopped crying started playing with each other as if they no longer 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 is a huge risk factor for suicide.”
For more about why mental 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. We gave people who were severely suicidal, very low of a narcotic drug, buprenorphine car buprenorphine for four weeks. We discovered that tiny, doses of buprenorphine, which are too low to treat physical pain, help many of become less suicidal.”
For more information about these study results, here.
note
“Some GPCRs can be activated by two different drugs at the same time. And when this happens, the result may be different for what happens when they’re activated by just one drug.”
For more about how GPCRs may be activated by two different drugs at the same time, see here.