Opioid overdose and tolerance: is the recruitment of β-arrestin to the µ-receptor involved?
Opioid overdose and tolerance: is the recruitment of β-arrestin to the µ-receptor involved?
复制标题
阿片类药物过量和耐受性：是否涉及β-抑制蛋白向μ-受体的募集？
DOI：
10.1038/s41386-021-01121-3
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Christie,MacdonaldJ
中科院分区：
文献类型：
--
作者：
Gillis,Alexander;Christie,MacdonaldJ
寻找更安全的阿片类镇痛剂，减少耐受性，成瘾性和致命的过量，由于呼吸抑制的责任已经遇到了一个世纪的成功很小。这种追求的最新迭代之一是更安全阿片类药物的G蛋白信号偏差假设。这表明，不能将β-抑制蛋白募集到μ-阿片受体（莫尔）的阿片激动剂不会产生阿片诱导的呼吸抑制（OIRD）、耐受或成瘾的严重副作用，因为受体激活期间β-抑制蛋白的募集触发介导这些不良反应的信号级联。这一想法导致了对多种pupirin G蛋白偏向的莫尔激动剂的描述，包括现在被FDA批准的药物oliceridine。该假设是在二十年前开始的一系列重要研究之后提出的，这些研究似乎表明突变小鼠中β-arrestin 2（也称为arrestin-3）的种系缺失大大降低了吗啡诱导的OIRD [1]、镇痛耐受性和其他不良反应（参见[2]）。然而，至少四个独立实验室的最新研究未能重现β-arrestin 2敲除小鼠中钝OIRD的原始观察结果[3，4]。在表达不募集β-抑制蛋白的磷酸化缺陷型莫尔突变体的敲入小鼠（实际上是G蛋白偏向的莫尔小鼠）中进行的研究类似地未能发现当在莫尔活化期间不募集β-抑制蛋白时OIRD的任何减少（参见参考文献104）。[2]）。在这个问题的神经精神药理学，他等。[5]重复OIRD的阴性结果，重要的是，为现在未经证实的原始发现提供了合理的解释。问题似乎在于，最初的实验是在具有混合品系背景的β-抑制蛋白2敲除小鼠上进行的，殖民地是由敲除129只雄性小鼠与野生型C57 BL/6雌性小鼠杂交而形成的。He等人[5]现在报道了129/SvJ和C57 BL/6 J近交系小鼠品系之间呼吸的实质性差异，并且关键的是，在129/SvJ小鼠中对吗啡诱导的呼吸抑制具有抗性。由于原始研究中使用的小鼠仍处于混合129-C57 BL/6背景下，因此结果可能受到父本129品系特征的混淆。长期以来，人们一直知道这个问题可能会在转基因小鼠是通过实验室小鼠品系的杂交，然后进行有限的回交而获得的情况下产生假阳性。相比之下，最近的阴性研究都是在稳定的同类C57 BL/6 J背景下进行的，在几个独立的实验室中回交至少10代，消除了这种潜在的混淆。[5]然后进一步挑战β-arrestin 2信号以某种方式介导OIRD的概念，使用该小组先前开发的“回收MOR”（RMOR）突变小鼠模型。该小鼠表达莫尔/δ-阿片样物质（DOR）嵌合受体，其中莫尔的C-末端区域已与DOR的C-末端区域交换。He等人先前已经确定，吗啡比野生型莫尔更有效地将β-arrestin 2募集到突变型RMOR中。他们认为，如果β-arrestin 2信号确实介导OIRD，那么吗啡诱导的OIRD在RMOR小鼠中应该更严重。由于吗啡在RMOR小鼠中产生镇痛作用的效力更强，因此用于比较的等镇痛剂量的吗啡并未产生比野生型小鼠更差的OIRD，这证明增强β-抑制蛋白2的募集不会产生增强的不良作用。这一结果进一步…
The search for safer opioid analgesics that have reduced liability for tolerance, addiction, and lethal overdose due to respiratory depression has met with little success for well over a century. One of the more recent iterations of this pursuit has been the G protein signalling bias hypothesis of safer opioids. This posits that opioid agonists which fail to recruit β-arrestins to the µ-opioid receptor (MOR) will not produce the severe side effects of opioid-induced respiratory depression (OIRD), tolerance, or addiction because the recruitment of β-arrestins during receptor activation triggers signalling cascades that mediate these adverse effects. This idea has led to the description of multiple putatively G protein-biased MOR agonists, including a drug now approved by the FDA, oliceridine. The hypothesis was proposed following a prominent series of studies beginning two decades ago, that appeared to show that germline deletion of β-arrestin2 (also known as arrestin-3) in a mutant mouse greatly reduced morphine-induced OIRD [1], analgesic tolerance and other adverse effects (see [2]). However, more recent studies in at least four independent laboratories have failed to reproduce the original observation of blunted OIRD in the β-arrestin2 knockout mice [3, 4]. Studies in knock-in mice expressing a phosphorylation-deficient mutant MOR that does not recruit β-arrestins, effectively a G protein-biased MOR mouse, have similarly failed to find any reduction in OIRD when β-arrestins are not recruited during MOR activation (see ref.[2]). In this issue of Neuropsychopharmacology, He et al.[5] replicate this negative result for OIRD and, importantly, provide a plausible explanation for the now unsubstantiated original findings. The problem appears to be that the initial experiments were performed on β-arrestin2 knockout mice with a mixed strain background, the colony being formed from the interbreeding of knockout 129 male mice with wild-type C57BL/6 females. He et al.[5] now report substantial differences in respiration between 129/SvJ and C57BL/6J inbred mouse strains and, critically, a resistance to morphine-induced respiratory depression in 129/SvJ mice. As the mice used in the original studies remained on a mixed 129-C57BL/6 background, the results may have been confounded by paternal 129 strain characteristics. This issue has long been known to potentially yield false positives in situations where genetically modified mice are derived by the inter-crossing of laboratory mouse strains, followed by limited backcrossing. By contrast, the more recent negative studies have uniformly been performed on a stable, congenic C57BL/6J background, following backcrossing in several independent laboratories for at least ten generations, eliminating this potential confound.He et al.[5] then go further to challenge the notion that β-arrestin2 signalling in some way mediates OIRD using a ‘recycling MOR’(RMOR) mutant mouse model the group previously developed. This mouse expresses a MOR/δ-opioid (DOR) chimeric receptor, in which the C-terminal region of MOR has been swapped with that of the DOR. He et al. had previously established that morphine much more effectively recruits β-arrestin2 to the mutant RMOR than in the wild type MOR. They argue that if β-arrestin2 signalling indeed mediates OIRD, then morphine-induced OIRD should be more severe in the RMOR mouse. Equi-analgesic doses of morphine, used for comparison as morphine is more potent in producing analgesia in RMOR mice, did not produce worse OIRD than in wild-type mice, evidence that enhancing recruitment of β-arrestin2 does not produce enhanced adverse effects. This result further …