《自然》：开发更安全的阿片类药物

资讯作者：Weill Cornell Medical College

编辑翻译：奇奇

本文献于2021年10月13日发表在国际著名期刊《自然》上。文中研究人员探索了阿片类药物过度滥用的原因，通过使用现代科学技术为开发更安全的阿片类药物铺平了道路，有望降低阿片类药物过量导致的死亡。

研究人员可能已经发现了如何制造出更安全的阿片类药物的新方法。设计一种新的阿片类药物以绕过大脑中感觉快乐的部分，但保留其止痛特性，这让阿片类药物成为最有效的止痛药之一。

在10月13日发表在《自然》上的一篇研究中，研究人员探索了阿片类药物是如何变得如此大范围滥用的。

“我们发现了mu-阿片类药物如何调节反馈的一个主要来源，提供了系统如何运作的蓝图。”Daniel Castro说。他是该研究的主要作者，也是华盛顿大学医学院麻醉学和疼痛医学的讲师。该研究也是布鲁卡斯实验室(该实验室研究神经回路如何影响动机性行为)的一部分。

他们研究了大脑中被称为伏隔核的部分，这是大脑反馈回路中的一个关键区域。当我们做任何被认为是有益的事情时，多巴胺神经元会投射到大脑的这个区域，让我们感觉良好并想要更多。

华盛顿大学麻醉学和疼痛医学教授Michael Brucha说：“像吗啡这样的mu-阿片类药物作用于大脑中的特定受体，就像锁的钥匙一样。而我们分离出了一条新的大脑通道，这些受体在这里能发挥强大的作用，促进反馈消耗行为。”

他们发现，阿片类受体位于大脑中一个被称为中缝背核的区域，该区域位于脑干的后部。其作用是改变中缝和伏隔核（位于大脑前部）之间的交流。Castro说：“这一发现非常出乎意料。”

Bruchas说，之前的研究只关注了mu-阿片类受体如何改变多巴胺传递。Castro也提到，为了制造一种安全的阿片类药物，制药公司需要绕过或创造一种方法，来让药物的作用偏离中缝背核通道，从而转向伏隔核通道。

研究人员专注于研究阿片肽受体MOPR。当受到刺激时，MOPR会改变呼吸、镇痛、反馈行为，并可能导致药物的滥用和过量使用。MOPR是导致滥用阿片类止痛药和阿片类药物最常见的阿片类肽受体。改变它的功能会导致痛苦的戒断，并促使进一步的滥用行为。这就是为什么人们无法戒除海洛因或吗啡等毒品的原因。

研究人员能够通过使用非常现代的神经科学工具和药理学来发现这一现象。这些工具包括体内钙成像、CRISPR Cas-9(一项获得2020年诺贝尔奖的技术)、荧光原位杂交和光遗传学，这是一种彻底改变神经科学的方法。

这项研究为进一步发现大脑系统调节或调节的其他行为开辟了众多新途径，为阿片类药物或其他缓解疼痛的药物提供了潜在的新途径。

与此同时，阿片类药物的流行已经持续了20多年。第一波始于20世纪90年代阿片类药物处方的增加，出现更多阿片类药物过量死亡。第二波始于2010年，涉及海洛因相关的过量死亡的迅速增加，而现在我们正处于第三波合成阿片类药物的浪潮中。

根据美国疾控中心的数据，自1999年以来，涉及阿片类药物(包括处方阿片类药物、海洛因和合成阿片类药物(如芬太尼))的过量死亡人数增加了六倍多。2019年，涉及阿片类药物的过量用药导致近5万人死亡，其中近73%的死亡涉及合成阿片类药物。布鲁卡斯实验室和华盛顿大学神经生物学中心的同事们正在积极探索药物滥用和心理健康障碍新疗法背后的科学。

英文原文

Study Could Pave Way For Creating Safer Opioids

Researchers may have uncovered new answers on how to create safer opioids. Design a new opioid to bypass the part of brain that feels pleasure, but retain the analgesic properties, which make opioids one of the most effective pain relievers.

In a study published in Nature Oct. 13, researchers looked at how opioids may have become so widely abused.

"We identified a major source of how mu-opioids mediate reward," said lead author Daniel Castro, acting instructor in anesthesiology and pain medicine at UW Medicine and part of The Bruchas Lab, which examines how neural circuits affect motivated behaviors. "We provided a blueprint of how the system works."

They studied a part of the brain called the nucleus accumbens, a key region in the reward circuit of the brain. When we do anything that is considered rewarding, dopamine neurons project to this area of the brain and make us feel good and want more.

"Mu-Opioids like morphine act on specific receptors in the brain, like keys in a lock," said Michael Bruchas, UW professor of anesthesiology and pain medicine. "We isolated a new brain pathway where these receptors exert powerful effects to promote reward consumption behavior."

They found that opioid receptors are in a part of the brain called the dorsal raphe nucleus located towards the back of the brain by the brain stem. They act to alter the communication between the raphe and nucleus accumbens, which are in the front of the brain. "This finding was pretty unexpected," said Castro.

Bruchas said prior work had focused solely on how mu-opioid receptors alter dopamine transmission. To create a safe opioid, pharmaceutical companies would need to either bypass or create ways to bias the drug's effect away from the dorsal raphe to nucleus accumbens pathway, Castro said.

The researchers focused on the opioid peptide receptor MOPR. When stimulated, MOPR alters respiration, analgesia, reward behavior, and can induce substance abuse and overdose. This is the most common opioid peptide receptor engaged by opioid pain killers and opiates which are abused. Altering its function can cause agonizing withdrawal and promotes further abuse. This is why people can become unable to abstain from using drugs like heroin or morphine.

Researchers were able to make this discovery by using very modern neuroscience tools and pharmacology. The tools include in vivo calcium imaging, CRISPR Cas-9 (a technique that won the 2020 Nobel Prize), fluorescent in situ hybridization and optogenetics, an approach that has revolutionized neuroscience.

The study opens many new avenues for more discovery on what other behaviors the system mediates or moderates, providing potentially new avenues for opioids or other drugs, which relieve pain.

Meanwhile, the opioid epidemic has been going on for more than 20 years. The first wave began with increased prescribing of opioids in the 1990s, with overdose deaths involving prescription opioids. The second wave began in 2010, with rapid increases in overdose deaths involving heroin, and now we are in a third wave of synthetic opioids.

According to the Centers for Disease Control, overdose deaths involving opioids, including prescription opioids, heroin, and synthetic opioids (like fentanyl), have increased over six times since 1999. Overdoses involving opioids killed nearly 50,000 people in 2019, and nearly 73% of those deaths involved synthetic opioids. The Bruchas Lab, along with colleagues in the UW Center for the Neurobiology, of Addiction, Pain and Emotion are actively pursuing the science behind new treatments for drug abuse and mental health disorders.

参考文献

Daniel C. Castro et al, An endogenous opioid circuit determines state-dependent reward consumption, Nature (2021).

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