Fentanyl addiction: the brain pathways behind the opioid crisis

Nick Petrić Howe

Welcome back to the Nature Podcast, this week: why fentanyl is so addictive...

Lizzie Gibney

…and why babies are suing the government of South Korea. I’m Lizzie Gibney.

Nick Petrić Howe

And I'm Nick Petrić Howe.

Nick Petrić Howe

Opioids, like fentanyl, are behind tens of thousands of deaths every year in the US alone, and that is in large part down to their very addictive nature. The drugs have two main effects on the brain that contribute to this: one, they make you feel good — they reward you for taking them, and two, if you stop taking them you feel bad — you get withdrawal.

And whilst these two effects are known to drive addiction, the underlying neuronal mechanism is unclear. And that’s a problem, because whilst these drugs have great potential to do harm, they are also incredibly useful for pain relief. A better understanding of what’s going on in the brain could allow scientists to design drugs that are less addictive, whilst still keeping their benefits.

And that is precisely what Christian Lüscher from the University of Geneva in Switzerland, and his collaborators, have done - in mice - using the particularly potent drug, fentanyl. Here’s Christian.

Christian Lüscher

So far, when you look in the textbook, the explanation that is usually given is that opioids very strongly activates the dopamine system. And when they do so for some time, weeks, or even months, and then all of a sudden, they're not available, that system is sort of exhausted. And then you have a situation where you have not enough dopamine. And that would explain why people have this aversive state and they feel down. Now our work looked into this and we needed to do this in mice, because only there we can actually do all these molecular manipulations. And the first observation we made, which was very surprising is when you take out the protein, the receptor that is responsible for that positive reinforcement, in the reward system, the withdrawal is still normal. So there is there's still dependence and when the animal no longer has access to an opioid, they will show all the signs of withdrawal syndrome. So the– the explanation that it is the same system that causes the positive reinforcement, as well as the negative reinforcement didn't seem to hold. And so that was the beginning of our study.

Nick Petrić Howe

So rather than there just being this one system that does both these things, there seem to be two different systems that do this sort of like withdrawal part and this reward pathway. How did you identify what was going on in these two different pathways?

Christian Lüscher

So we put the mice in situation where they will go into withdrawal. And we looked in many, many different brain regions, which ones were active. You can do this by monitoring a gene a so called immediate early gene that reflects the neuronal activity. And we had then a few candidate areas where something really interesting is going on during withdrawal, one of which was the central amygdala. And that's why we focused our attention then on this particular part of the brain.

Nick Petrić Howe

And what is the central amygdala normally involved in?

Christian Lüscher

So it's involved in fear responses, in anxiety. And so it's, of course, the brain regions that people know very well. What we have been able to contribute with this, that we identified the population of cells that express the receptor for the opiates, it's called the µ-opioid receptor. And that was unknown until then how exactly these cells are located in the central amygdala. And that is how we were able to identify that it is actually those cells, which are the entry gate if you will, of this negative reinforcement for opiates.

Nick Petrić Howe

And this is in contrast to the other one that's doing the more sort of positive reward side.

Christian Lüscher

Sure. So, then we now change from a model where one system would be responsible for both the positive and the negative reinforcement to a system where you would have two distinct circuits that mediate one and the other.

Nick Petrić Howe

And not only the identify these neurons and their relative locations in the brain, but you also manipulated them to show that there was a very causal mechanism going on here.

Christian Lüscher

That's the beauty of current modern circuit neuroscience. You cannot observe what happens in the cells but then you have actually tools to manipulate and these are largely optogenetic tools. That is, you can manipulate those cells by putting in ion channels that are light sensitive and you can either activate or inhibit the cells. And so, I guess the crucial experiment that really indicates causality was when we were able to put an opsin into these cells of the central amygdala, that activates those cells, and we made them active continuously. And we showed that this is very similar to the aversive state that the animal feels in opiate withdrawal. And so the animal then was given the opportunity to press a lever to pause this activation, and that they learned very quickly. So, this is precisely the definition of negative reinforcement, you do an action to alleviate an aversive state. And what's more, this mechanism is then also sensitive to the injection of fentanyl. So, we could block this behaviour by exposing the animal a little bit to fentanyl.

Nick Petrić Howe

So, what do you think this means for our sort of understanding of opioids and addiction, that there are these two pathways?

Christian Lüscher

So for first, it's a gain in knowledge we better understand and now we can focus on the cellular mechanism and the molecular mechanisms. So it is conceivable that we then design drugs that would activate one or not the other. So, this is in the larger picture of trying to parse the relevant circuits that mediate specific symptoms of opiates. So for cor– for the opiates, the– the effect that we usually look for is to use them as painkillers. So, to reduce the pain that's yet in a different brain area but it is now important to see that we have additional two mechanisms that are involved and not one. And that will sort of give us new ideas on how to do selective new compounds that would basically do pain, to reduce the pain but not induce addiction. And it could also help us to better design substitution therapies, which is the cornerstone of opioid use disorder treatment. When people suffer from that they usually receive methadone, or in some countries, even heroin as a substitution drug. And now that we know how heroin and methadone activates these both circuits, we can improve those substitution therapies.

Nick Petrić Howe

And you know, you mentioned a couple of different opioids there. This study was about fentanyl, so do you think this sort of mechanism is broadly applicable to opioids?

Christian Lüscher

You're right, we need to formally test this. But from all we know, it's the exact same receptors that is activated, because when you take out the new receptors, all effects of the opiates are gone. And so, by extension, we are confident that this applies not only to fentanyl, but also to other opiates. The reason why we chose fentanyl is because it is a drug of public concern. But it is also a very rapidly active drug and that helps us to parse the effects. The faster a drug, the easier it is to see under experimental conditions.

Nick Petrić Howe

And you know, this study was in mice, what do you think needs to be done to translate this to humans?

Christian Lüscher

Well, we know that these receptors and these brain circuits also exists in humans, and we can image them with functional technologies such as functional MRI, and I think our clinical colleagues now can use our sort of blueprint of what one has to look for, to confirm or not whether the same mechanisms apply to human people with addiction.

Nick Petrić Howe

That was Christian Lüscher, from the University of Geneva, in Switzerland. For more on that story, including a link to Christian’s latest paper, published in Nature, check out the show notes.

Lizzie Gibney

Coming up, why babies are taking the South Korean government to court. Right now, though, it’s time for the Research Highlights, with Dan Fox.

<music>

Dan Fox

The model of the blood-brain barrier made by combining two organoids could transform how scientists studied drug delivery to the brain. Organoids are groups of lab-grown cells that together form structures resembling an organ. By combining organoids, researchers can make ‘assembloids’ allowing them to study complex biological systems. In this case, a team wanted to learn more about the blood-brain barrier, the layer of cells that regulates which chemicals can pass from the bloodstream into the brain. To replicate the barrier, they combined blood vessel organoids with brain organoids. The blood vessels grew into the brain tissue creating networks of capillaries, and the team found that the same types of cell were present in the same places in both the ‘assembloid’ and the human blood-brain barrier. The researchers also created models using stem cells from people with a genetic disorder that causes the blood-brain barrier to fail. These yielded ‘assembloids’ that replicated the donors’ disease. Read that research in full in Cell Stem Cell.

<music>

Dan Fox

An edible gel based on milk protein can both prevent and treat alcohol intoxication in mice. Harmful alcohol consumption leads to millions of deaths each year. And while treatments exist for severe intoxication, many of them need to be injected directly into a vein and provide only temporary relief from symptoms. Now, researchers have developed an alternative, by combining single iron atoms with nanometre-scale threads of a milk protein that is a by-product of cheesemaking. The team found that the gel could reduce alcohol levels in the blood of intoxicated mice and even prevent mice from becoming intoxicated in the first place. They say that their approach has potential for human use in a clinical setting. If you want to read that paper, you can find it in Nature Nanotechnology.

<music>

Lizzie Gibney

Finally on the show, it’s time for the Briefing Chat where we discuss a couple of articles that have been featured in the Nature Briefing. Nick, what have you been reading about this time?

Nick Petrić Howe

Well, I've been reading about how babies are suing the South Korean government. And this was a story I was reading in Nature.

Lizzie Gibney

I'm so intrigued by this.

Nick Petrić Howe

Well, I should say it's not literally the babies taking the government to court is their parents using them as the plaintiff in this particular case. And it's about climate change. So, you've probably heard the various different climate change cases against governments for not doing their part or not doing enough in the view of those people to tackle climate change. And the idea is that for these younger folk it’s their futures that are being ruined. So, it may have a bit more of an effect on the government to say like, hey, you know, you're infringing on our human rights by not doing enough.

Lizzie Gibney

And is this somewhat unprecedented? Have babies taken people to court before?

Nick Petrić Howe

So, children across the world have actually taken governments to court. I think babies is quite unusual and, in this case, there's actually an unborn child as well who's one of the plaintiffs involved, obviously, again, it's the parents it's not literally the unborn child. But the idea, like I say, is that tackling climate change should protect future generations, and it's their– and it's their futures that will be affected if we don't do enough against climate change.

Lizzie Gibney

Yeah, it makes sense. What are the South Korean government doing or not doing that, you know, these families, including the babies want to happen?

Nick Petrić Howe

So currently, the South Korean government's targets are to reduce their emissions by 40% below their 2018 levels by 2030. Which sounds like a lot but if every country did that, that would still commit us to three degrees of warming by the end of the century. And you know, that's beyond the sort of limits that were agreed at Paris. And so, the argument here is that is insufficient, so they want to see more action. And this is done at a particular time as well, because this year, the Korean government will have to present their revised climate targets to the United Nations. And so, the people involved in this case, hope it will convince the government to, you know, be a bit more ambitious for the next 2035 target.

Lizzie Gibney

So, is this mostly a, you know, a public relations thing to get support for these kinds of changes to their targets? Or, you know, in the actual case, is there some kind of potential outcome that sees the government having to what I guess give a huge payout or something? Like what legally could happen if the families win?

Nick Petrić Howe

So, if there was a constitutional ruling that the South Korean government's targets were insufficient, they would have to enhance their climate ambition. So, there could be a very direct–

Lizzie Gibney

–it could force their hand to do something–

Nick Petrić Howe

–basically force their hand. And this has been seen, like across the world, as I said, like there have been other such cases, like in Switzerland, there was a famous one where similar things occurred. But the interesting thing about this one, as well, is this is the first case of its kind in East Asia — this really hasn't been done there. And the people involved are really hopeful that this will provoke more of these kinds of litigations against governments in East Asia, because really, we need everyone in the world involved. But in the past, in East Asia, people have seen litigation as a last resort, and this may make them reconsider how they use litigation.

Lizzy Gibney

We often think of with climate change, you know, there not been much we can do as an individual, but I guess this is one of the things you can do is sue your government.

Nick Petrić Howe

No, exactly, and the people involved in this case are quite optimistic as well. They say even if they lose this case, it's provoking a conversation is provoking social awareness and it could start change happening more and more.

Lizzie Gibney

Shall we talk about my story next?

Nick Petrić Howe

Yeah, let's do it. What have you been reading this week?

Lizzie Gibney

Well, it's literally my own story. Little bit cheeky. I bought my own story, so it's obviously by me in Nature. And this is about a new kind of nuclear power source, a heater based on the radioactive decay of an element called americium, which is actually a by-product of nuclear waste. And that's going on the European Space Agency's ExoMars mission, and Europe has never had its own one of these before. And no one's ever made one of these kind of nuclear heaters out of this particular element, americium, before either, so it's– it's a double first.

Nick Petrić Howe

Yeah, a lot of firsts going on here. But I guess, first of all, what is this heater going to be used for? Literally just heating the spacecraft? Or is there something more?

Lizzie Gibney

That right. So, it can get very, very cold in space, and to operate all kinds of components you need a heater. And this is very, very long lasting. That's the beauty of these radioactive decay-kind of heaters. So as the americium decays, it just releases heat. And in this case, it's actually going to be warming things within the landing platform. So, you have the kind of mothership that gets you out there to Mars, and then you have the lander comes out of that and lands and then that turns into a landing platform, that then ejects the rover out onto the surface. So that's the Rosalind Franklin rover. So there are going to be some similar kind of heaters made by NASA on the rover, but the ones made by Europe, these new pioneering ones are going to be on the landing platform itself. So it says slightly complimentary, it's not– it's not– it's not the big guns, they haven't put them yet on the rover, which is where they'd be really, really, really important. But they’re still doing an important job there on this landing platform. So they're keeping the landing platform going for much longer than it probably would do otherwise.

Nick Petrić Howe

And why would you need to have the landing platform I guess, sort of heated up? Mars is pretty cold, I gather, but what is the advantage?

Lizzie Gibney

Exactly, so it is cold there, so it will be going to Mars with its own batteries that only lasts a certain amount of time. This will keep the batteries warm and that means that the lander will have power for longer. So if there's a problem, say or there's some issue with unfurling the landing platform and getting the rover out, the rover derives all its power from the landing platform before it's deployed on the surface, and it gets out of solar panels. So this will mean basically that anything that goes wrong with the rover exiting out onto the surface, we have a little bit more of a window to save the mission. So it could turn out to be really important.

Nick Petrić Howe

And are there extra considerations they need to make sort of sending nuclear material into space? I mean, space missions are quite dangerous, at the best of time.

Lizzie Gibney

Hugely. So until now only NASA and Roscosmos, the Russian Space Agency have made these kinds of nuclear-powered heaters, and similar batteries. So, ESA is not quite ready to do the battery-kind where you turn the heat into electricity, but it's getting there as well. But so far, it's always been NASA or Russia. And they have made theirs from plutonium and they have supplied everyone else. So, in previous years, previous ESA missions, they've just use American or Russian heaters and batteries. What happened here with ExoMars, of course, is it was a collaboration with Russia. And then following Russia's invasion of Ukraine, that partnership was severed. And so, ESA has had to go back to the drawing board on a lot of fronts and figure out how to make this mission work. So, this is one tiny glimmer of opportunity in there and that they've said, okay, you know, what we're gonna do, we don't have the Russian heaters anymore, we're gonna use our own new pioneering type.

Now, I realised I’ve gone off your question which was about how difficult is to make these and that is to say that very, very difficult, so they've only had plutonium ones up until now. And they require a huge amount of safety checks and certification before you can fly them. Obviously, what you're doing is effectively putting something radioactive on the top of a massive rocket, which is just another kind of fancy word for a bomb, really, and shooting it up into space. Okay, so they have to be really, really well encased so that they could withstand almost anything happening during launch. So those processes are going on right now. There's been some research teams that have been working on this since about 2009 on, you know there are so many different stages, how do we get this the americium, how do we get it? Well, it comes from nuclear waste, but can you take it out nuclear waste, and convert it into little kind of fuel pellets? You know, how do you do that? Then how do you build a device around it, because it's a lot, you get a lot less power for your gramme than you do with plutonium, which is what they've used till now. So, you need to just redesign the whole thing around that you need a bigger volume. So, they've been doing that. And then now we're in the kind of final stages, which is making sure it's all really safe. And so, this is going to launch in 2028. So, it feels like a long way off but I think it's gonna go in the blink of an eye, isn't it. So, they've probably got a lot of work to do.

Nick Petrić Howe

Well, hopefully we can come back in four years and see where it's at, then and hopefully all goes well for them. But I think that's all we've got time for on the Briefing Chat today. Listeners, for more on those stories, check out the show notes for some links and a link of where you can sign up to the Nature Briefing to get more like them.

Lizzie Gibney

That's all for this week, as always you can keep in touch with us on X, we're @NaturePodcast, or you can send an email to podcast@nature.com.

Nick Petrić Howe

And if you've enjoyed listening, don't forget you can always drop us a review wherever you get your podcasts. I'm Nick Petrić Howe.

Lizzie Gibney

And I'm Lizzie Gibney. Thanks for listening