I’m Yoram Youvel. I’m 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 my mother and my grandfather on the door and asked me out to the corridor.
“Your father’s very sick,” my mother said. “Your father is dead.” And then I felt it. A crushing pain in my chest. I still feel a glimpse of it whenever I think of my father.
He a doctor, a scientist, a paratrooper. He was a young, strong, happy, healthy man. He was hero. And his death broke my heart.
Do you remember the pain you when someone broke your heart? When your best friend or your mother died? Or man you loved told you that he doesn’t love you anymore. probably do.
But why do we feel mental pain all? And what’s the relationship between physical and mental pain? most importantly, how can we make mental pain better? Together with scientists and physicians, I 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. Twelve years after my father died, I was a graduate student at Dr. Eric Kandel’s lab at Columbia University. Eric, won the Nobel Prize 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 protein that’s part of a synapse. And synapses are structures through which nerve cells with each other. Now that receptor was a GPCR. That’s a protein coupled receptor. I’ll explain what this means in a minute and then you’ll understand what this stack markers is doing here.
And when I did that, I didn’t really realize work on that receptor, which seemed completely unrelated to future work as a clinical psychiatrist, would one day help us in our search for better treatments physical and mental pain.
Now a big step along that way was the work of Panksepp, my other great scientific mentor. In a 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 a sound is called the separation distress cry. And it goes like this.
(Imitates puppy wailing)
Puppies do it, kittens do it, babies do it. All mammals do it when they’re in pain or when they miss their mothers. And we all know how this cry makes us feel inside.
Panksepp and his colleagues traced the brain circuits that produce these cries in guinea pigs, they made a startling discovery. That these are the very same circuits that are active when humans sad and when they experience depression. And these circuits are also of the brain’s pain matrix that mediates our sensations of physical and mental pain.
But why are we born with terrible gift hardwired into our brains? Well, probably because any pain, mental pain is an alarm system. Its task is to prevent damage. When babies lose their mothers, hurt and they cry. Which brings their mothers back, and it also makes them seek their mothers. In the wild, this is life-saving. Puppies babies cannot survive without their mothers.
So now we know why we have mental pain. It is the glue that us together in couples, in families and communities. And when 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 can answer an age-old question that poets and philosophers have asking for thousands 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 the block a couple of times, personally, I it’s worth it.
But we’re not entirely defenseless against pain because brains produce endorphins or endogenous opioids, our very own feel-good molecules, the natural remedy both physical and mental pain. Endorphins are released in the brain during aerobic exercise or when we’re close to we love, and immediately after severe injuries.
And we know what endorphins do, they attach to special receptors in the brain, and the important among them are mu opioid receptors. And just like the I worked on in Kandel’s lab, mu opioid receptors are GPCR.
Here’s how they work. Like all GPCRs, mu opioid receptors made of seven spirals or loops that are stacked together, sticking through both sides of the cell membrane. Like this, OK.
And when attach to mu opioid receptors from the outside, they cause them change their shape. Like this, OK? And this triggers series of events inside the neurons which eventually ease pain.
Now, forget the molecules for a second. When you hug you love who is suffering from severe physical or mental pain, you cause her brain to release endorphins. They attach to opioid receptors in her synapses and turn them on, and they soothe her pain.
And yet, sometimes mental pain gets so intense that no amount love can soothe it. But medicine has powerful drugs that can ease any pain. These are the narcotics or opioids like morphine. Narcotics work mainly by activating mu opioid receptors.
footnote
But if so, can narcotics also treat the pain of separation? It was Jaak Panksepp found the answer. Panksepp gave his puppies in a experiment tiny, tiny doses of morphine, lower than the lowest doses that 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 now. When mental pain in humans becomes too intense to bear people, some people, will do anything to stop it, try to kill themselves. Indeed, and I’m saying this as a clinical psychiatrist, mental pain is a huge risk factor for suicide.
footnote
But if narcotics physical pain, and if they can soothe the mental 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 narcotic drug, called buprenorphine, for four weeks.
We discovered tiny, tiny doses of buprenorphine, which are too low to treat physical pain, helped many of them become suicidal. But narcotics are extremely dangerous drugs. They may cause addiction, and they’re lethal in overdose. In contrast, endorphins are not lethal in overdose, and they’re much less likely to addiction. So narcotics and endorphins probably activate mu opioid receptors in different ways.
Now, if could find drugs that activate mu opioid receptors in a way that resembles how endorphins activate them, we might 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 I had learned Kandel’s lab many, many years ago.
footnote
Some 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. So our research team then used molecular computing technologies create a detailed virtual model of the human mu receptor. And then, with the help of programs known molecular docking algorithms, we screened thousands of existing drugs on a model of the receptor.
Eventually, we found a way to teach an old dog, that’s the human mu opioid receptor, some new tricks. We found two drugs that not narcotics, and they work together in very, very doses to activate the human mu opioid receptor.
I’m not you their names, because we still have to run many tests clinical trials before we can be certain that their does exactly what we think it does. But both of these drugs have been around for many, many years, and they’ve been used by millions 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 hardwired into our brains. And mental pain is an essential part of mourning and depression sadness. And when it gets severe enough, it can actually people suicidal. Endorphins are brain’s natural remedy for physical and mental pain, they work mainly, not exclusively, but mainly by activating mu opioid receptors.
Now, narcotics also mu opioid receptors, but in a way that causes addiction and can lead to death. And this is why narcotics are so dangerous. New technologies have helped us identify two existing drugs that together may treat physical mental pain without some of the severe side effects narcotics. However, this is still a work in progress. It would be a 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 family and friends who are in severe physical or mental pain.
Thank you very much.
(Applause)
Footnotes
note
“Panksepp his puppies, in a separation experiment, tiny, tiny doses morphine – lower than the lowest doses that are used to treat physical pain. And puppies immediately stopped crying and started playing with each other as if they no longer miss their mothers.”
According to results from this 1978 study, morphine-treated puppies were quite alert and about normally while isolated from their mothers.
note
“Unbearable mental pain is a huge risk factor for suicide.”
For more information about mental pain is a significant risk factor for suicide, see here.
note
“A years ago, together with Panksepp and other colleagues, my team conducted a clinical trial. We gave people who severely suicidal, very low doses of a narcotic drug, buprenorphine car for four weeks. We discovered that tiny, tiny doses of buprenorphine, which are too low to treat physical pain, help many of them become 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 be different for what happens when they’re activated by one drug.”
For more information about how GPCRs may be activated two different drugs at the same time, see here.