I’m Yoram Youvel. I’m a psychiatrist neuroscientist at the Hebrew University of Jerusalem. And when was 14 years old, my father died. I was sitting in class when my 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 I felt it. A crushing pain in my chest. I 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. He was my hero. his death broke my heart.
Do you remember the pain you felt when broke your heart? When your best friend or your died? Or the man you loved told you that he doesn’t love you anymore. You probably do.
But why do we feel mental pain at all? And what’s the relationship physical and mental pain? And most importantly, how can we make mental pain better? Together with many scientists physicians, I spent years searching for answers to these questions.
Now, growing up, I never heard the words, “We want you to be doctor and a brain scientist like your father.” But somehow that’s what happened. Twelve after my father died, I was a graduate student at Dr. Eric Kandel’s at Columbia University. Eric, who won the Nobel Prize for his work on the molecular basis of memory, was the ultimate mentor. Passionate, and inspiring.
Under his guidance, I studied a receptor. It’s a that’s part of a synapse. And synapses are structures through which cells communicate with each other. Now that receptor was a GPCR. That’s G protein coupled receptor. I’ll explain what this means in a minute and then you’ll understand what this stack of markers is 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 help us in our search for treatments for physical and mental pain.
Now a big step along that way was the work of Jaak Panksepp, my other great scientific mentor. In a classical experiment, Panksepp puppies from their mothers for 15 minutes. Never more than because he loved animals. When puppies lose their mothers, they make a sound which 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 do it when they’re in pain or when 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, and they made a startling discovery. That these are the very same circuits are active when humans feel sad and when they experience depression. And these circuits are also part of the brain’s pain 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 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 wild, this is life-saving. Puppies and babies cannot survive without their mothers.
So we know why we have mental pain. It is the glue keeps us together in couples, in families and communities. And when someone we goes 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 asking for thousands of years.
Does love always hurt? What you think? Does love always hurt? Yes, love always hurts, of course. that’s what it’s supposed to do. Mental pain is 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 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 natural remedy both physical and mental pain. Endorphins are released in the brain during exercise or when we’re close to someone we love, and immediately after severe injuries.
And we now know endorphins do, they attach to special receptors 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 seven or loops that are stacked together, sticking through both sides of the membrane. Like this, OK.
And when endorphins attach to mu opioid receptors from the outside, they cause them to change their shape. Like this, OK? And this a series of events inside the neurons which eventually ease the pain.
Now, forget the molecules for a second. When you 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 her synapses and turn them on, and they soothe pain.
And yet, sometimes mental pain gets so intense no amount of love can soothe it. But medicine has powerful drugs that can ease any physical pain. are the narcotics or opioids like morphine. Narcotics work mainly by activating mu opioid receptors.
footnote
But so, can narcotics also treat the pain of separation? It was Jaak Panksepp who the answer. Panksepp gave his puppies in a separation experiment tiny, tiny doses of morphine, lower than the lowest doses that are used treat physical pain, and his puppies immediately stopped crying and started playing with each other as if they no longer their mothers.
Let’s go to humans now. When mental pain in humans becomes too intense to bear people, some people, will do anything stop it, even try to kill themselves. Indeed, and I’m saying this as a clinical psychiatrist, unbearable mental pain is a huge risk factor suicide.
footnote
But if narcotics treat physical pain, and if they can the mental pain of separation, can they also help suicidal people become less suicidal? A few years ago, together with Panksepp 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 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 to cause addiction. So narcotics and endorphins probably activate mu opioid receptors in different ways.
Now, if we could find drugs that activate mu opioid receptors a way that resembles how endorphins activate them, we might be able treat physical and mental pain without some of the dangerous 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 the same time. And when this happens, the result may different from what happens when they’re activated by just one drug. So our team then used molecular computing technologies to create a detailed model of the human mu opioid receptor. And then, with help of programs known as molecular docking algorithms, we screened of existing drugs on a virtual model of the receptor.
Eventually, we a way to teach an old dog, that’s the mu opioid 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 telling 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 of these drugs been around for many, many years, and they’ve been used millions of people. So we know that they’re safe 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 essential part of mourning and depression and sadness. And when it gets severe enough, it can actually make people suicidal. Endorphins are brain’s natural remedy for and mental pain, and they work mainly, not exclusively, but mainly activating mu opioid receptors.
Now, narcotics also activate mu opioid receptors, but in a that causes addiction and can lead to death. And this is why narcotics are so dangerous. New computational technologies helped us identify two existing drugs that together may treat physical mental pain without some of the severe side effects of narcotics. However, is still a work in progress. It would be a few before it may become an approved treatment.
But, and 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 much.
(Applause)
Footnotes
note
“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 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 and moved about normally while isolated from their mothers.
note
“Unbearable mental pain a huge risk factor for suicide.”
For more information about why mental pain a significant risk factor for suicide, see here.
note
“A few years ago, together with Panksepp and other colleagues, my research team conducted clinical trial. We gave people who were severely suicidal, very low doses of a drug, buprenorphine car buprenorphine for four weeks. We discovered that tiny, tiny doses of buprenorphine, which are too to treat physical pain, help many of them become less suicidal.”
For more information about these results, see here.
note
“Some GPCRs can be activated by two different drugs at the time. And when this happens, the result may be different what happens when they’re activated by just one drug.”
For more information about how GPCRs may be activated by two different drugs at same time, see here.