I’m Yoram Youvel. I’m a psychiatrist and neuroscientist at the Hebrew of Jerusalem. And when I was 14 years old, my father died. I was sitting in class when mother and my grandfather knocked on the door and asked me out to the corridor.
“Your father’s very sick,” my mother said. “Your father is dead.” 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 a doctor, scientist, a paratrooper. He was a young, strong, happy, healthy man. He my hero. And his death broke my heart.
Do you remember the pain you felt someone broke your heart? When your best friend or your mother died? Or the you loved told you that he doesn’t love you anymore. You probably do.
But why do feel mental pain at all? And what’s the relationship physical and mental pain? And most importantly, how can we mental pain better? Together with many scientists and physicians, I spent years searching for answers 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 graduate student at Dr. 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 guidance, I studied a receptor. It’s a protein that’s part of a synapse. And are structures through which nerve cells communicate with each other. Now that was a GPCR. That’s a G protein coupled receptor. I’ll explain what this in a minute and then you’ll understand what this stack of is doing here.
And when I did that, I didn’t really realize that work on receptor, which seemed completely unrelated to my future work as clinical psychiatrist, would one day help us in our search better treatments for physical and mental pain.
Now a big step along 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 that because he loved animals. When puppies lose their mothers, make a sound which is called the separation distress cry. And it goes like this.
(Imitates puppy wailing)
Puppies do it, 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 then traced brain circuits that produce these cries in guinea pigs, and they made a startling discovery. That these the very same circuits that are active when humans feel sad and when experience depression. And these circuits are also part of the brain’s pain matrix that mediates our sensations of physical and pain.
But why are we born with this 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, they hurt and cry. Which brings their mothers back, and it also makes them seek their mothers. In the wild, this life-saving. Puppies and babies cannot survive without their mothers.
So now we know why have mental pain. It is the glue that keeps us together in couples, in families and communities. And someone we love goes away or is taken away from us, it’s this 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 of years.
Does love always hurt? What do you think? Does always hurt? Yes, love always hurts, of course. Because that’s what it’s supposed to do. Mental pain is simply high price, the very high price, that we pay for our ability 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 our brains produce endorphins or endogenous opioids, our very own feel-good molecules, the natural remedy for both 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 what 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 opioid receptors are GPCR.
Here’s they work. Like all GPCRs, mu opioid receptors are made of seven spirals or 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 to change their shape. Like this, OK? And this triggers series of events inside the neurons which eventually ease the pain.
Now, forget the molecules a second. When you hug someone you love who is suffering from severe physical or pain, you actually cause her brain to release endorphins. They to mu opioid receptors in her synapses and turn them on, and they soothe her pain.
And yet, sometimes pain gets so intense that no amount of love can soothe it. But medicine has powerful drugs that can ease physical pain. These are the narcotics or opioids like morphine. Narcotics work by activating mu opioid receptors.
footnote
But if so, can 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 to treat physical pain, his puppies immediately stopped crying and started playing with each other as if they no longer miss mothers.
Let’s go to humans now. When mental 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 the mental pain of separation, can they also help suicidal become less suicidal? A few years ago, together with Panksepp and other colleagues, research team conducted a clinical trial. We gave people who were severely suicidal very doses of a narcotic drug, called buprenorphine, for four weeks.
We discovered that tiny, tiny doses of buprenorphine, are too low to treat physical pain, helped many of them less suicidal. But narcotics are extremely dangerous drugs. They may cause addiction, and they’re lethal in overdose. In contrast, endorphins not lethal in overdose, and they’re much less likely to cause addiction. So narcotics and endorphins probably mu opioid receptors in different ways.
Now, if we could drugs that activate mu opioid receptors in a way that resembles how endorphins activate them, we might be able to treat and mental pain without some of the dangerous side effects of narcotics. And when my 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 the same time. And when this happens, the result be different from what happens when they’re activated by just one drug. So our research team then used molecular technologies to create a detailed virtual model of the human mu opioid receptor. And then, with the of programs known as molecular docking algorithms, we screened of existing drugs on a virtual model of the receptor.
Eventually, we found 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 in very, very small doses to activate the human mu opioid receptor.
I’m not telling you their names, because we have to run many tests and clinical trials before we be certain that their combination does exactly what we think it does. But both of drugs have been around for many, many years, and they’ve been by 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 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, and work mainly, not exclusively, but mainly by activating mu opioid receptors.
Now, narcotics also activate mu opioid receptors, but a way that causes addiction and can lead to death. And this is why narcotics are so dangerous. New computational have helped us identify two existing drugs 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 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 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 – lower than the lowest doses that are used to treat physical pain. his puppies immediately stopped crying and started playing with each other as if they no longer miss their mothers.”
According to results from 1978 study, morphine-treated puppies were quite alert and moved about normally while from their mothers.
note
“Unbearable mental pain is a huge risk factor for suicide.”
For more information about why mental is a significant risk factor for suicide, see here.
note
“A few years ago, together with Panksepp and other colleagues, my research team a clinical trial. We gave people who were severely suicidal, very low doses of a narcotic drug, buprenorphine buprenorphine for four weeks. We discovered that tiny, tiny doses of buprenorphine, which are too low to treat physical pain, help many of them become less suicidal.”
For more about these study results, see here.
note
“Some GPCRs be activated by two different drugs at the same time. And when 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 two different drugs at the same time, here.