I’m Yoram Youvel. I’m a psychiatrist neuroscientist at the Hebrew University of Jerusalem. And when I 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 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 can still feel a glimpse of it I think of my father.
He was a doctor, scientist, a paratrooper. He was a young, strong, happy, healthy man. He was my hero. And his death my heart.
Do you remember the pain you felt when someone broke heart? When your best friend or your mother died? the 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 and mental pain? And most importantly, how we make mental pain better? Together with many scientists and physicians, I spent years searching for answers to questions.
Now, growing up, I never heard the words, “We want you to a doctor and a brain scientist like your father.” But 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 Prize 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 are structures through nerve cells communicate 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 of markers doing here.
And when I did that, I didn’t really realize that work on that receptor, seemed completely unrelated to my future work as a clinical psychiatrist, would one day us in our search for better treatments for physical and mental pain.
Now 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 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 young mammals it when they’re in pain or when they miss their mothers. And we all know how this cry makes us inside.
Panksepp and his colleagues then traced the brain circuits that produce these cries in guinea pigs, and made a startling discovery. That these are the very same circuits that are active 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 are we born with this terrible gift hardwired into our brains? Well, probably because like any pain, mental is an alarm system. Its task is to prevent damage. babies lose their mothers, they hurt and they cry. Which brings their back, and it also makes them seek their mothers. In the wild, this is life-saving. Puppies and babies cannot survive without their mothers.
So we know why we have mental pain. It is glue that keeps us together in couples, in families and communities. when someone we love goes away or is taken away from 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 thousands years.
Does love always hurt? What do you think? Does love always hurt? Yes, love always hurts, of course. Because that’s what it’s to 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 around the block a couple of times, personally, I think it’s worth it.
But we’re not defenseless against pain because our brains produce endorphins or endogenous opioids, our very feel-good molecules, the natural remedy for both physical and mental pain. are released in the brain during aerobic exercise or when we’re close to someone 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 them are mu opioid receptors. And just like receptor I worked on in Kandel’s lab, mu opioid receptors are GPCR.
Here’s how work. Like all GPCRs, mu opioid receptors are made of seven spirals or loops that are together, sticking through both sides of the cell membrane. Like this, OK.
And when endorphins attach to mu opioid from the outside, they cause them to change their shape. Like this, OK? And this triggers a series of events inside the neurons which eventually ease the pain.
Now, forget the molecules for second. When you hug someone you love who is suffering from severe physical or mental pain, you actually her brain to release 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 soothe it. But medicine has powerful drugs that can ease any physical pain. These are the narcotics or opioids like morphine. Narcotics mainly by activating mu opioid receptors.
footnote
But if so, narcotics also treat the pain of separation? It was Jaak who found the answer. Panksepp gave his puppies in a experiment tiny, tiny doses of morphine, lower than the lowest doses that are used to treat pain, and his puppies immediately stopped crying and started with each other as if they no longer miss their mothers.
Let’s go to humans now. When 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 narcotics physical pain, and if they can soothe the mental pain of separation, can they also help suicidal people become less suicidal? A few years ago, together with Panksepp and other colleagues, my research team conducted a clinical trial. gave people who were severely suicidal very low doses a narcotic drug, called buprenorphine, for four weeks.
We discovered that tiny, tiny doses of buprenorphine, which are too low to treat physical pain, many of them become less suicidal. But narcotics are extremely dangerous drugs. They may cause addiction, and they’re in overdose. In contrast, endorphins are not lethal in overdose, and they’re much less likely cause addiction. So narcotics and endorphins probably activate mu opioid receptors in ways.
Now, if we could find drugs that activate mu opioid receptors in a way that resembles how endorphins activate them, we be able 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 learned in Kandel’s lab many, many ago.
footnote
Some GPCRs can be activated by two different drugs at the same time. And when this happens, the result may be different from what happens when they’re activated by just one drug. So our research team used molecular computing technologies to create a detailed virtual model of human mu opioid receptor. And then, with the help of programs known as docking algorithms, we screened thousands of existing drugs on a virtual model the receptor.
Eventually, we found a way to teach an old dog, that’s the human mu receptor, some new tricks. We found two drugs that are not narcotics, and they work together very, very small doses to activate the human mu opioid receptor.
I’m not you their names, because we still have to run many tests and clinical trials before we be certain that their combination does exactly what we think it does. But both these drugs have been around for many, many years, and they’ve been used millions of people. So we know that they’re safe for humans.
Here’s bottom line. Let’s summarize what we’ve seen. First and foremost, mental pain is real. It’s into our brains. And mental pain is an essential of mourning and depression and sadness. And when it gets severe enough, it can actually make people suicidal. Endorphins 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 is why narcotics are so dangerous. New computational technologies have us identify two existing drugs that together may treat physical and pain without some of the severe side effects of narcotics. However, this 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 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 doses that are used to treat physical pain. And his puppies immediately stopped and started playing with each other as if they no longer miss mothers.”
According to results from this 1978 study, morphine-treated puppies 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 a risk factor for suicide, see here.
note
“A few years ago, together with Panksepp and other colleagues, my research team conducted a clinical trial. gave people who were severely suicidal, very low doses of a drug, buprenorphine car buprenorphine for four weeks. We discovered 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 two drugs at the same time. And when this happens, the result may different for what happens when they’re activated by just one drug.”
For more information about GPCRs may be activated by two different drugs at the time, see here.