I’m Yoram Youvel. I’m a psychiatrist and neuroscientist at the Hebrew of Jerusalem. And when I was 14 years old, father died. I was sitting in class when my mother and my grandfather knocked on the door and asked me out to the corridor.
“Your father’s sick,” my mother said. “Your father is dead.” And then felt it. A crushing pain in my chest. I can still feel 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. was my hero. And his death broke my heart.
Do you remember pain you felt when someone broke your heart? When your best friend or your mother died? the man you loved told you that he doesn’t love you anymore. probably do.
But why 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, spent years searching for answers to these questions.
Now, growing up, I never heard the words, “We 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 Columbia University. Eric, who won the Nobel for his work on the molecular basis of memory, was ultimate mentor. Passionate, energetic and inspiring.
Under his guidance, I studied a receptor. It’s a protein that’s part of a synapse. And synapses structures through which nerve cells communicate with each other. Now that receptor was a GPCR. That’s a G coupled receptor. I’ll explain what this means in a minute and then you’ll understand what this of markers is doing here.
And when I did that, I didn’t really realize that work on that receptor, which seemed completely unrelated my future work as a clinical psychiatrist, would one day help us in our search for better for physical and mental pain.
Now a big step along that way was the work of Jaak Panksepp, my other great mentor. In a classical experiment, Panksepp 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 distress cry. And it 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 miss mothers. And we all know how this 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. That these are very same circuits that are active when humans feel 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 we born with this terrible gift hardwired into our brains? Well, probably because like any pain, mental pain is an system. Its task is to prevent damage. When babies lose mothers, they hurt and they cry. Which brings their mothers back, and it also makes them seek mothers. In the wild, this is life-saving. Puppies and babies cannot survive without their mothers.
So now we know why have mental pain. It is the glue that keeps us together in couples, in families and communities. And someone we love goes away or is taken away from us, it’s this pain which us back together. And once we realize this, then we can answer an age-old question that and philosophers have been asking for thousands of years.
Does love always hurt? do you 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 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 pain our brains produce endorphins or endogenous opioids, our very own feel-good molecules, the natural remedy for both physical and pain. Endorphins are released in the brain during aerobic 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 in the brain, and the most important among them are mu 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 of the cell membrane. Like this, OK.
And when endorphins attach to mu opioid receptors the outside, they cause them to change their shape. Like this, OK? And this triggers a series events inside the neurons which eventually ease the pain.
Now, forget the molecules for a second. When you hug someone you love who is suffering from severe physical or mental pain, you actually cause her brain to endorphins. They attach to mu opioid receptors in her synapses turn them on, and they soothe her pain.
And yet, sometimes mental gets so intense that no amount of love can it. But medicine has powerful drugs that can ease physical pain. These are the narcotics or opioids like morphine. work mainly by activating mu opioid receptors.
footnote
But if so, can narcotics treat the pain of separation? It was Jaak Panksepp who found the answer. Panksepp his puppies in a separation experiment tiny, tiny doses of morphine, lower than lowest doses that are used to treat physical pain, his puppies immediately stopped crying and started playing with each other as if they no miss their mothers.
Let’s go to humans now. When mental pain 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 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, 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 were suicidal very low doses of a narcotic drug, called buprenorphine, for four weeks.
We discovered that tiny, tiny doses of buprenorphine, which too low to treat physical pain, helped many of them become suicidal. But narcotics are extremely dangerous drugs. They may addiction, and they’re lethal in overdose. In contrast, endorphins not lethal in overdose, and they’re much less likely cause addiction. So narcotics and endorphins probably activate mu opioid receptors different ways.
Now, if we could find drugs that mu opioid receptors in a way that resembles how endorphins activate them, we might be able to treat physical and mental pain without of the dangerous side effects of narcotics. And when my research team came this conclusion, I suddenly remembered what I had learned in Kandel’s lab many, many ago.
footnote
Some GPCRs can be activated by two different drugs at the time. And when this happens, the result may be different from happens when they’re activated by just one drug. So research team then used molecular computing technologies to create a detailed virtual model of the human mu receptor. And then, with the help of programs known as molecular docking algorithms, we screened thousands of existing on a virtual model of the receptor.
Eventually, we found a way to an old dog, that’s the human mu opioid receptor, some new tricks. found two drugs that are not narcotics, and they together in very, very small doses to 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 that their combination does what we think it does. But both of these have been around for many, many years, and 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. First foremost, mental pain is real. It’s hardwired into our brains. And mental is an essential part of mourning and depression and sadness. And when gets severe enough, it can actually make people suicidal. are brain’s natural remedy for physical and mental pain, and they work mainly, not exclusively, but mainly by activating mu opioid receptors.
Now, narcotics also activate opioid receptors, but in a way that causes addiction can lead to death. And this is why narcotics are so dangerous. New computational technologies have helped us identify two existing drugs that may treat physical and mental pain without some of 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 the last thing I’m going say, regardless of drugs, you have the ability to help family and friends who are severe physical or mental pain.
Thank you very much.
(Applause)
Footnotes
note
“Panksepp gave puppies, in a separation experiment, tiny, tiny doses of morphine – lower than the lowest doses that are used to physical pain. And his puppies immediately 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 and moved about normally while isolated from their mothers.
note
“Unbearable mental pain is a huge risk factor suicide.”
For more information about why mental pain is significant risk factor for suicide, see here.
note
“A few years ago, together with Panksepp and other colleagues, research team conducted a clinical trial. We gave people who were severely suicidal, very low doses 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 them become less suicidal.”
For more information about study results, see here.
note
“Some GPCRs can be by two different drugs at the same time. And when this happens, result may be 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.