ß-arrestin 2 germline knockout does not attenuate opioid respiratory depression.
ß-arrestin 2 germline knockout does not attenuate opioid respiratory depression.
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DOI：
10.7554/elife.62552
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发表时间：
2021-05-18
期刊：
影响因子：
7.7
通讯作者：
Yackle K
中科院分区：
文献类型：
--
作者：
Bachmutsky I;Wei XP;Durand A;Yackle K
阿片类药物可能是医学上最有效的止痛药。然而，在1999年至2018年期间，美国有40多万人死于阿片类药物过量。过量的阿片类药物会使呼吸变得致命的缓慢和浅，这种副作用被称为阿片类药物引起的呼吸抑制。这把双刃剑激发了开发新型治疗方法的愿望，这种治疗方法可以在不抑制呼吸的情况下提供阿片类镇痛药。其中一种方法是设计所谓的“偏倚激动剂”，通过微阿片受体（MOR）下游的一些但不是所有途径发出信号，MOR是吗啡和其他阿片镇痛药的靶点。这一理论基础源于一项研究，该研究表明莫尔诱导的ß-抑制素2依赖信号是阿片类药物呼吸抑制的原因，而腺苷酸环化酶抑制产生镇痛。为了验证这一重要的结果，激发了“偏倚激动剂”的方法，我们重新检查了ß-arrest 2缺陷小鼠的呼吸，反而发现ß-arrest 2和阿片类药物呼吸抑制之间没有联系。这一结果表明，“偏倚激动剂”对呼吸的任何减弱作用都是通过一种尚未确定的机制实现的。阿片类药物由于其强大的止痛特性而经常被开处方。然而，如果滥用，这些化合物会导致呼吸变得危险地缓慢和浅：1999年至2018年期间，仅在美国就有40多万人死于阿片类药物过量。这些药物究竟是如何影响呼吸的还不清楚。已知的是，阿片类药物通过与细胞表面的特定受体结合而起作用，这一事件对许多生化途径具有连锁反应。其中，2005年发表的一项研究发现，β-抑制素2通路与改变呼吸有关。这促使人们努力寻找类阿片药物，这些药物不会干扰这一途径，保留其缓解疼痛但不影响呼吸的能力。然而，新的证据对这项研究的结论提出了质疑。作为回应，Bachmutsky、Wei等人试图复制2005年的原始发现。研究人员使用了具有严格控制的遗传背景的小鼠，其中β-抑制蛋白2通路的基因要么存在，要么不存在。两组动物在正常情况下和服用阿片类药物后的呼吸模式相似。结果表明β-抑制素2与阿片类药物诱导的呼吸抑制无关。这些发现表明，开发不影响β-抑制素2通路的阿片类药物的研究是基于一个错误的前提。精确地针对药物的分子机制来避免抑制呼吸可能仍然是一种有效的方法，但需要更多的研究来确定正确的途径。
Opioids are perhaps the most effective analgesics in medicine. However, between 1999 and 2018, over 400,000 people in the United States died from opioid overdose. Excessive opioids make breathing lethally slow and shallow, a side-effect called opioid-induced respiratory depression. This doubled-edged sword has sparked the desire to develop novel therapeutics that provide opioid-like analgesia without depressing breathing. One such approach has been the design of so-called ‘biased agonists’ that signal through some, but not all pathways downstream of the µ-opioid receptor (MOR), the target of morphine and other opioid analgesics. This rationale stems from a study suggesting that MOR-induced ß-arrestin 2 dependent signaling is responsible for opioid respiratory depression, whereas adenylyl cyclase inhibition produces analgesia. To verify this important result that motivated the ‘biased agonist’ approach, we re-examined breathing in ß-arrestin 2-deficient mice and instead find no connection between ß-arrestin 2 and opioid respiratory depression. This result suggests that any attenuated effect of ‘biased agonists’ on breathing is through an as-yet defined mechanism. Opioid drugs are commonly prescribed due to their powerful painkilling properties. However, when misused, these compounds can cause breathing to become dangerously slow and shallow: between 1999 and 2018, over 400,000 people died from opioid drug overdoses in the United States alone. Exactly how the drugs affect breathing remains unclear. What is known is that opioids work by binding to specific receptors at the surface of cells, an event which has a ripple effect on many biochemical pathways. Amongst these, research published in 2005 identified the β-arrestin 2 pathway as being responsible for altering breathing. This spurred efforts to find opioid-like drugs that would not interfere with the pathway, retaining their ability relieve pain but without affecting breathing. However, new evidence is now shedding doubt on the conclusions of this study. In response, Bachmutsky, Wei et al. attempted to replicate the original 2005 findings. Mice with carefully controlled genetic background were used, in which the genes for the β-arrestin 2 pathway were either present or absent. Both groups of animals had similar breathing patterns under normal conditions and after receiving an opioid drug. The results suggest β-arrestin 2 is not involved in opioid-induced breathing suppression. These findings demonstrate that research to develop opioid-like drugs that do not affect the β-arrestin 2 pathway are based on a false premise. Precisely targeting a drug’s molecular mechanisms to avoid suppressing breathing may still be a valid approach, but more research is needed to identify the right pathways.