Potential for Kappa-Opioid Receptor Agonists to Engineer Nonaddictive Analgesics: A Narrative Review.
Potential for Kappa-Opioid Receptor Agonists to Engineer Nonaddictive Analgesics: A Narrative Review.
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DOI：
10.1213/ane.0000000000005309
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发表时间：
2021-02-01
影响因子：
5.7
通讯作者：
Siderovski DP
中科院分区：
文献类型：
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作者：
Kaski SW;White AN;Gross JD;Siderovski DP
处方阿片类镇痛药的一个严重不良反应是对这些镇痛药和也激活μ阿片受体（莫尔）的非法药物（如海洛因）成瘾。阿片类药物使用障碍（OUD）和阿片类药物过量死亡代表了当前美国的健康危机，而阿片类镇痛药的处方对这一危机起了重要作用。虽然处方类阿片是高效镇痛剂，但目前还没有一种简便的方法可以在不产生成瘾风险的情况下长期使用。如果由MOR靶向镇痛剂引起的成瘾可以通过混合新的“抗成瘾”成分来阻断，该成分不会减少镇痛作用并且不会引入其自身的治疗限制性副作用，则可以维持（甚至增强）处方阿片类药物用于治疗疼痛的持续临床使用，而不是减少。在这篇叙述性评论中，我们将这一假设置于背景中，首先简要概述了当前美国阿片类药物成瘾危机。两个关键的受体在OUD的发展，莫尔和κ阿片受体（KOR）的神经生物学，然后讨论突出的神经解剖学特征和电路，从这些受体的信号转导在于反对-创造机会，药理学干预，减少成瘾的潜力莫尔激动。在探索新的潜在途径（如偏向性KOR激动剂）之前，考虑了混合莫尔/KOR激动剂的既往研究结果。新的临床前数据突出表明，G蛋白偏向KOR激动剂纳呋拉芬降低了MOR靶向镇痛药的奖励特性，并增强了MOR靶向镇痛药诱导的抗伤害感受。最后，我们讨论了最近的发现，即G蛋白信号调节器（即RGS 12）是KOR信号偏差的关键组成部分，提出了另一种药物发现目标，旨在确定单一药物或添加到传统阿片类镇痛药中的佐剂，可以减少或消除后者药物的成瘾潜力。
A serious adverse effect of prescription opioid analgesics is addiction, both to these analgesics and to illicit drugs like heroin that also activate the mu 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 “anti-addiction” 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 two key receptors in OUD development, MOR and the kappa 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 pre-clinical 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 anti-nociception. 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 towards 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.
DOI：
10.1177/0269881120944160
发表时间：
2020-12
期刊：
Journal of psychopharmacology (Oxford, England)
影响因子：
--
作者：
White AN;Gross JD;Kaski SW;Trexler KR;Wix KA;Wetsel WC;Kinsey SG;Siderovski DP;Setola V
通讯作者：
Setola V