From the Departments of Neuroscience and Behavioral Medicine & Psychiatry, West Virginia University, Morgantown, West Virginia.
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina.
Anesth Analg. 2021 Feb 1;132(2):406-419. doi: 10.1213/ANE.0000000000005309.
A serious adverse effect of prescription opioid analgesics is addiction, both to these analgesics and to illicit drugs like heroin that also activate the µ-opioid receptor (MOR). Opioid use disorder (OUD) and opioid overdose deaths represent a current American health crisis, and the prescription of opioid analgesics has contributed significantly to this crisis. While prescription opioids are highly effective analgesics, there currently exists no facile way to use them for extended periods without the risk of addiction. If addiction caused by MOR-targeting analgesics could be blocked by blending in a new "antiaddiction" ingredient that does not diminish analgesia and does not introduce its own therapeutically limiting side effects, then continued clinical use of prescription opioids for treating pain could be maintained (or even enhanced) instead of curtailed. In this narrative review, we contextualize this hypothesis, first with a brief overview of the current American opioid addiction crisis. The neurobiology of 2 key receptors in OUD development, MOR and the κ-opioid receptor (KOR), is then discussed to highlight the neuroanatomical features and circuitry in which signal transduction from these receptors lie in opposition-creating opportunities for pharmacological intervention in curtailing the addictive potential of MOR agonism. Prior findings with mixed MOR/KOR agonists are considered before exploring new potential avenues such as biased KOR agonists. New preclinical data are highlighted, demonstrating that the G protein-biased KOR agonist nalfurafine reduces the rewarding properties of MOR-targeting analgesics and enhances MOR-targeting analgesic-induced antinociception. Finally, we discuss the recent discovery that a regulator of G protein signaling (namely, RGS12) is a key component of signaling bias at KOR, presenting another drug discovery target toward identifying a single agent or adjuvant to be added to traditional opioid analgesics that could reduce or eliminate the addictive potential of the latter drug.
处方类阿片类镇痛药的一个严重不良反应是成瘾，包括对这些镇痛药和海洛因等同样激活μ-阿片受体（MOR）的非法药物的成瘾。阿片类药物使用障碍（OUD）和阿片类药物过量死亡是当前美国的健康危机，而处方类阿片类药物的使用对此危机有重大贡献。虽然处方类阿片类药物是非常有效的镇痛药，但目前还没有一种简单的方法可以在不产生成瘾风险的情况下长期使用它们。如果可以通过混合一种新的“抗成瘾”成分来阻止 MOR 靶向镇痛药引起的成瘾，这种成分既不会降低镇痛效果，也不会引入自身具有治疗限制的副作用，那么继续临床使用处方类阿片类药物治疗疼痛就可以得到维持（甚至增强），而不是被削减。在这篇叙述性综述中，我们首先简要概述了当前美国阿片类药物成瘾危机，以此为背景来阐述这一假设。然后讨论了 OUD 发展中 2 个关键受体，即 MOR 和 κ-阿片受体（KOR）的神经生物学，以突出这些受体信号转导所在的神经解剖学特征和回路，为通过药理学干预来限制 MOR 激动剂的成瘾潜力提供机会。在探讨新的潜在途径，如偏向性 KOR 激动剂之前，我们考虑了混合 MOR/KOR 激动剂的先前发现。突出了新的临床前数据，表明 G 蛋白偏向性 KOR 激动剂那呋拉啡减少了 MOR 靶向镇痛药的奖赏特性，并增强了 MOR 靶向镇痛药引起的镇痛作用。最后，我们讨论了最近发现的一种 G 蛋白信号调节因子（即 RGS12）是 KOR 信号转导偏向的关键组成部分，这为识别一种可添加到传统阿片类镇痛药中的单一药物或佐剂提供了另一个药物发现目标，该药物或佐剂可以降低或消除后者药物的成瘾潜力。
