Podcasts 科学播客 | 「芬太尼为什么会成瘾？揭示阿片危机背后的神经环路」

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.

像芬太尼这样的阿片类药物，每年仅在美国就导致成千上万的死亡，而这主要归因于它们的强烈成瘾性。这些药物对脑部有两个主要影响，促成了成瘾的形成：一方面，它们让人感觉良好，服用它们会产生奖励效应；另一方面，如果停止服用，它们会让人感觉不适，出现戒断症状。虽然这两种效应已被认为是成瘾的主要驱动力，但其背后的神经机制仍不清楚。这是一个问题，因为尽管这些药物具有极大的危害潜力，但它们在疼痛缓解方面也非常有用。更深入了解脑部的具体机制，可能帮助科学家设计出更少成瘾性、但仍保留止痛功效的药物。这正是瑞士日内瓦大学的Christian Lüscher及其团队在小鼠身上所做的研究，他们使用了特别强效的药物——芬太尼。接下来是Christian的介绍。

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.

到目前为止，教科书中通常给出的解释是，阿片类药物会非常强烈地激活多巴胺系统。当它们激活这个系统一段时间（几周甚至几个月）后，突然不再可用时，这个系统会有些耗竭，结果就是多巴胺不足，这可以解释为什么人们会感到厌恶和消沉。然而，我们的研究对此进行了深入探讨，并选择使用小鼠进行实验，因为只有这样我们才能进行所有的分子操作。我们首次观察到的一个非常意外的现象是，当我们去除负责正向强化的受体蛋白时，动物的戒断反应仍然正常。因此，尽管没有阿片类药物，动物依然表现出戒断综合征的所有迹象。因此，认为同一系统既导致正向强化又导致负向强化的解释似乎并不成立。这就是我们研究的起点。

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?

因此，与其说只有一个系统同时负责这两种作用，倒不如说似乎存在两个不同的系统：一个负责戒断反应，另一个负责奖励路径。你们是如何识别这两个不同通路中发生的情况的呢？

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.

我们将小鼠置于会引发戒断反应的环境中，并观察了许多不同的脑区，看看哪些区域处于活跃状态。我们通过监测一种称为“即时早期基因”的基因来反映神经元活动。结果我们发现了一些候选区域，在戒断期间这些区域发生了有趣的变化，其中一个就是中央杏仁体。因此，我们将注意力集中在这个特定的脑区。

Nick Petrić Howe

And what is the central amygdala normally involved in?

中央杏仁体通常涉及哪些功能？

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.

中央杏仁体参与恐惧反应和焦虑，当然，这是人们非常熟悉的脑区。我们所做的贡献是识别出表达阿片类药物受体（称为μ-阿片受体）的细胞群体。在此之前，尚不清楚这些细胞在中央杏仁体中的确切位置。正是通过这个发现，我们能够确认这些细胞实际上是阿片类药物负向强化的“入口”。

Nick Petrić Howe

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

这与负责正向奖励的另一条通路形成对比。

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.

没错。因此，我们现在从一个单一系统负责正向和负向强化的模型，转变为一个由两个不同的回路分别调节正向和负向强化的模型。

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.

不仅识别了这些神经元及其在脑中的相对位置，你们还对它们进行了操控，以证明这里存在一个因果机制。

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.

这正是现代回路神经科学的美妙之处。虽然不能直接观察细胞内发生的事情，但实际上是有工具可以进行操作的，主要是光遗传学工具。也就是说，你可以通过在这些细胞中植入光敏离子通道来操控它们，从而激活或抑制细胞。因此，我认为一个关键实验非常清楚地表明了因果关系：我们能够将一种视蛋白（opsin）植入中央杏仁体的细胞中，以持续激活这些细胞。我们发现，这种激活与动物在阿片类药物戒断时所感受到的厌恶状态非常相似。于是，动物被给予按杠杆暂停这种激活的机会，并且它们学得非常快。这正是负向强化的定义：通过采取某个行动来减轻厌恶状态。此外，这个机制对芬太尼的注射也很敏感。因此，我们可以通过让动物接触少量芬太尼来阻止这种行为。

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?

你认为这两个通路的发现对我们理解阿片类药物和成瘾意味着什么？

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.

首先，这是一项知识上的进步，让我们更好地理解了阿片类药物的作用机制，能够集中研究细胞和分子机制。因此，可以想象，我们将设计出激活一种通路而不激活另一种通路的药物。在更大背景下，这项研究旨在解析介导阿片类药物特定症状的相关回路。对于阿片类药物，我们通常关注的效果是用它们作为止痛药，以减轻疼痛，而疼痛发生在不同的脑区。现在重要的是看到我们有两个参与机制，而不是只有一个。这将为我们提供新思路，设计出选择性的新化合物，既能减轻疼痛，又不会导致成瘾。此外，这还可能帮助我们更好地设计替代疗法，这在阿片类药物使用障碍的治疗中至关重要。当人们遭受这种情况时，他们通常会接受美沙酮治疗，或在一些国家使用海洛因作为替代药物。现在我们知道海洛因和美沙酮如何激活这两个回路，我们就能改进这些替代疗法。

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?

你提到了一些不同的阿片类药物。这项研究是关于芬太尼的，你认为这种机制在阿片类药物中普遍适用吗？

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.

你说得对，我们需要正式测试这一点。但根据我们所了解的，它们激活的确是相同的受体，因为当我们去除μ-阿片受体时，阿片类药物的所有效果都会消失。因此，我们有理由相信，这不仅适用于芬太尼，也适用于其他阿片类药物。我们选择芬太尼的原因是因为它是公众关注的药物，同时它也是一种作用迅速的药物，这有助于我们解析其效果。药物作用越快，在实验条件下观察就越容易。

Nick Petrić Howe

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

这项研究是在小鼠身上进行的，你认为需要做些什么才能将其转化为对人类的研究？

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.

我们知道这些受体和脑回路在人类中也存在，并且我们可以使用功能性技术（如功能性磁共振成像）来进行成像。我认为我们的临床同事可以利用我们所提供的蓝图，寻找相关机制，以确认这些机制是否适用于有成瘾问题的人类。

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.

以上是瑞士日内瓦大学的Christian Lüscher的介绍。想要了解更多关于这个故事的信息，包括Christian最新论文的链接，欢迎查看节目说明。