I’m Youvel. I’m a psychiatrist and neuroscientist at the Hebrew University of Jerusalem. And when was 14 years old, my father died. I was in class when my mother and my grandfather knocked on the door and me out to the corridor.
“Your father’s very sick,” my said. “Your father is dead.” And then I felt it. A crushing pain in my chest. I can 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 my hero. And his death broke my heart.
Do you remember the pain you felt when someone broke your heart? When your friend or your mother died? Or the man you told you that he doesn’t love you anymore. You probably do.
But why do we feel mental pain all? And what’s the relationship between physical and mental pain? And most importantly, how can we make mental pain better? with many scientists and physicians, I spent years searching answers to these questions.
Now, growing up, I never heard the words, “We want you to be a doctor and a brain scientist like father.” But somehow that’s what happened. Twelve years after my father died, I was a student at Dr. Eric Kandel’s lab at Columbia University. Eric, who won the Nobel Prize for his work on the molecular basis memory, was the 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 communicate with each other. that receptor was a GPCR. That’s a G protein coupled receptor. I’ll explain 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 on that receptor, which seemed completely unrelated to my future work as 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 great scientific mentor. In a classical experiment, Panksepp separated from their mothers for 15 minutes. Never more than that because he loved animals. When puppies their mothers, they make a sound which is called the separation distress cry. And it like this.
(Imitates puppy wailing)
Puppies do it, kittens do it, babies do it. All young mammals do it they’re in pain or when they miss their mothers. And we all know how cry makes us feel inside.
Panksepp and his colleagues then traced the brain circuits that produce cries in guinea pigs, and they made a startling discovery. That these the 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 of physical and mental pain.
But why are we born with this terrible gift into our brains? Well, probably because like any pain, mental pain is an alarm system. Its task is prevent damage. When babies lose their mothers, they hurt and they cry. Which brings their mothers back, it also makes them seek their mothers. In the wild, this is life-saving. and babies cannot survive without their mothers.
So now we know why we have pain. It is the glue that keeps us together in couples, in families and communities. when someone we love goes away or is taken 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 asking for thousands of years.
Does love always hurt? What do you think? Does love always hurt? Yes, love always hurts, of course. Because that’s it’s supposed to do. Mental pain is simply the high price, the very high price, that we pay for our to love. And personally, and, you know, I’ve been around the block a couple of times, personally, I think it’s it.
But we’re not entirely defenseless against pain because our brains endorphins or endogenous opioids, our very own feel-good molecules, the natural for 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 now know endorphins do, they attach to special receptors in the brain, and the most among them are mu opioid receptors. And just like the receptor I worked on in Kandel’s lab, mu opioid 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 endorphins attach to mu opioid receptors from the outside, they cause them to change their shape. Like this, OK? And this triggers a series of events inside neurons which eventually ease the pain.
Now, forget the molecules for a second. When hug someone you love who is suffering from severe physical or mental pain, you actually cause brain to release endorphins. They attach to mu opioid receptors in her synapses and turn on, and they soothe her pain.
And yet, sometimes mental pain gets so that no amount of love can soothe it. But medicine has powerful drugs can ease any physical pain. These are the narcotics or opioids like morphine. Narcotics work mainly by activating mu opioid receptors.
footnote
But if so, can also treat the pain of separation? It was Jaak Panksepp who found the answer. Panksepp gave his puppies a separation experiment tiny, tiny doses of morphine, lower the lowest doses that are used to treat physical pain, and his puppies immediately crying and started playing with each other as if 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 anything to stop it, even to kill themselves. Indeed, and I’m saying this as a clinical psychiatrist, unbearable mental pain a huge risk factor for suicide.
footnote
But if narcotics treat physical pain, and if they can soothe the mental pain of separation, can they also suicidal people become less suicidal? A few years ago, together with Panksepp and other colleagues, my research team conducted a clinical trial. We gave people who were severely suicidal low doses of a narcotic drug, called buprenorphine, for four weeks.
We 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 cause addiction, and they’re lethal in overdose. In contrast, endorphins are not in overdose, and they’re much less likely to cause addiction. So narcotics and endorphins probably activate mu receptors in different ways.
Now, if we could find drugs that mu opioid receptors in a way that resembles how endorphins activate them, we might be to treat physical and mental pain without some of the dangerous side effects of narcotics. when my research team came to this conclusion, I suddenly remembered what I learned in Kandel’s lab many, many years ago.
footnote
Some GPCRs be activated by two different drugs at the same time. And this happens, the result may be different from what happens they’re activated by just one drug. So our research then used molecular computing technologies to create a detailed virtual model the human mu opioid receptor. And then, with the help of programs known as molecular docking algorithms, screened thousands of existing drugs on a virtual model the receptor.
Eventually, we found a way to teach an dog, that’s the human mu opioid receptor, some new tricks. We found two drugs are not narcotics, and they work together in very, very small to activate the human mu opioid receptor.
I’m not telling you names, because we still have to run many tests clinical trials before we can be certain that their combination 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 of people. So we know that they’re safe for humans.
Here’s our 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 and sadness. And it gets severe enough, it can actually make people suicidal. Endorphins are brain’s natural remedy for physical and pain, and they work mainly, not exclusively, but mainly by activating mu opioid receptors.
Now, narcotics activate mu opioid receptors, but in a way that causes addiction and can lead to death. And this why narcotics are so dangerous. New computational technologies have helped us identify two existing that together may treat physical and mental pain without some of the severe side of narcotics. However, this is still a work in progress. It be a few years before it may become an approved treatment.
But, and this the last thing I’m going to 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 pain. And his puppies immediately stopped crying and started playing with each other as if they no longer miss mothers.”
According to results from this 1978 study, morphine-treated puppies were alert and moved about normally while isolated from their mothers.
note
“Unbearable mental is a huge risk factor for suicide.”
For more information about why mental pain is a significant risk factor for suicide, see here.
note
“A few years ago, with Panksepp and other colleagues, my research team conducted a clinical trial. We 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, which are too low to treat physical pain, help many them become less suicidal.”
For more information about these study results, see here.
note
“Some GPCRs can be activated two different drugs at the same 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 two different drugs at the same time, see here.