I’m Yoram Youvel. I’m a psychiatrist and neuroscientist at the University of Jerusalem. And when I was 14 years old, my died. I was sitting in class when my mother and my grandfather knocked on the door and asked me out to corridor.
“Your father’s very sick,” my mother said. “Your father is dead.” And then I felt it. A pain in my chest. I can still feel a glimpse of it whenever I of my father.
He was a doctor, a scientist, a paratrooper. was a young, strong, happy, healthy man. He was my hero. And his death broke my heart.
Do you remember the pain you felt when someone your heart? When your best friend or your mother died? Or man you loved told you that he doesn’t love you anymore. You probably do.
But why do we 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 want you to be a doctor and a brain like your father.” But somehow that’s what happened. Twelve years 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 the ultimate mentor. Passionate, energetic and inspiring.
Under his guidance, I studied receptor. It’s a protein that’s part of a synapse. And synapses are structures through nerve cells communicate with each other. Now that receptor was a GPCR. That’s a G protein coupled receptor. I’ll explain what this means in a minute then you’ll understand what this stack of markers is doing here.
And when 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 treatments physical and mental pain.
Now a big step along that way was the work of Jaak Panksepp, my great scientific mentor. In a classical experiment, Panksepp separated puppies their mothers for 15 minutes. Never more than that because he animals. When puppies lose their mothers, they make a which is called the separation distress cry. And it goes like this.
(Imitates puppy wailing)
Puppies do it, kittens do it, babies do it. young mammals do it when they’re in pain or they miss their mothers. And we all know how this cry makes us feel inside.
Panksepp his colleagues then traced the brain circuits that produce these cries guinea pigs, and they made a startling discovery. That these are the very same circuits that are when humans feel sad and when they experience depression. And these circuits are part of the brain’s pain matrix that mediates our sensations of physical and mental pain.
But why are we with this terrible gift hardwired into our brains? Well, probably because like 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 makes them their mothers. In the wild, this is life-saving. Puppies and babies cannot survive without their mothers.
So now we know we have mental pain. It is the glue that keeps us in couples, in families and communities. And when someone love goes away or is taken away from us, it’s this pain which draws us back together. once we realize this, then we can answer an age-old that poets and philosophers have been asking for thousands of years.
Does love hurt? What do you think? Does love always hurt? Yes, love hurts, of 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 the block a couple of times, personally, I think it’s worth it.
But we’re not entirely defenseless against pain because our produce endorphins or endogenous opioids, our very own feel-good molecules, the remedy for both physical and mental pain. Endorphins are released 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 to special receptors in the brain, and the most important among them mu opioid receptors. And just like the receptor I worked on in Kandel’s lab, opioid receptors are GPCR.
Here’s how they work. Like GPCRs, mu opioid receptors are made of seven spirals or loops that stacked together, sticking through both sides of the cell membrane. Like this, OK.
And endorphins attach to mu opioid receptors from the outside, they them to change their shape. Like this, OK? And this triggers a series of events inside the neurons which ease the pain.
Now, forget the molecules for a second. When you hug someone you love 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 her pain.
And yet, sometimes mental pain gets so intense that no amount of love can soothe it. But medicine has powerful drugs that ease any physical pain. These are the narcotics or opioids like morphine. Narcotics mainly by activating mu opioid receptors.
footnote
But so, can narcotics also treat the pain of separation? It was Jaak Panksepp who found the answer. Panksepp gave his in a separation experiment tiny, tiny doses of morphine, lower than the lowest doses that are to treat physical pain, and his puppies immediately stopped crying started playing with each other as if they no longer miss their mothers.
Let’s go to humans now. When mental pain in humans becomes too intense bear people, some people, will do anything to stop it, even try to kill themselves. Indeed, and I’m saying this as a clinical psychiatrist, unbearable mental pain is a huge risk for suicide.
footnote
But if narcotics treat physical pain, and if they can soothe the mental pain of separation, they also help suicidal people become less suicidal? A few years ago, with Panksepp and other colleagues, my research team conducted a 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 many of them become suicidal. But narcotics are extremely dangerous drugs. They may cause addiction, and they’re lethal in overdose. In contrast, are not lethal in overdose, and they’re much less likely to cause addiction. So narcotics and endorphins probably activate mu opioid in different ways.
Now, if we could find drugs that activate mu opioid receptors in way that resembles how endorphins activate them, we might be able to treat physical and mental pain some of the dangerous side effects of narcotics. And when my research team came to this conclusion, I remembered what I had learned in Kandel’s lab many, many years ago.
footnote
GPCRs can be activated by two different drugs at same time. And when this happens, the result may be different from happens when they’re activated by just one drug. So our research team then used molecular computing technologies to a detailed virtual model of the human mu opioid receptor. And then, with the help of programs known as molecular docking algorithms, we thousands of existing drugs on a virtual model of the receptor.
Eventually, we found way to teach an old dog, that’s the human mu opioid receptor, some new tricks. We found two drugs that are not narcotics, and they work together in very, very small doses to 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 of these drugs have been around for many, many years, and 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 and foremost, mental pain real. It’s hardwired into our brains. And mental pain is an essential of mourning and depression and sadness. And when it gets severe enough, it can make people suicidal. Endorphins are brain’s natural remedy for physical and mental pain, and work mainly, not exclusively, but mainly by activating mu opioid receptors.
Now, narcotics also activate mu opioid receptors, but in a way that addiction and can lead to death. And this is why narcotics are so dangerous. New computational technologies have us identify two existing drugs that together may treat physical and mental pain without some of the 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 last thing I’m going to say, regardless of drugs, you have the ability to help family and who are in severe physical 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 treat physical pain. And his puppies immediately stopped crying and started with each other as if they no longer miss their mothers.”
According to from this 1978 study, morphine-treated puppies were quite alert and moved about normally isolated from their mothers.
note
“Unbearable mental pain is a huge risk for suicide.”
For more information about why mental pain is significant risk factor for suicide, see here.
note
“A few years ago, together with Panksepp 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 weeks. We discovered that tiny, tiny doses of buprenorphine, are too low to treat physical pain, help many of them become less suicidal.”
For more information these study results, see here.
note
“Some GPCRs can be activated by two different drugs at the same time. And this happens, the result may be different for what happens they’re activated by just one drug.”
For more information about how GPCRs may be activated by different drugs at the same time, see here.