Assessment of the potential of novel and classical opioids to induce respiratory depression in mice
Assessment of the potential of novel and classical opioids to induce respiratory depression in mice
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DOI：
10.1111/bph.16199
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发表时间：
2023-08-22
影响因子：
7.3
通讯作者：
Canals，Meritxell
中科院分区：
文献类型：
--
作者：
Hill，Rob;Sanchez，Julie;Canals，Meritxell
阿片类药物诱导的呼吸抑制限制了μ阿片受体激动剂在临床环境中的使用，是阿片类药物过量死亡的主要原因。不同阿片类激动剂在超过产生镇痛的剂量下诱导呼吸抑制的相对潜力研究不足，尽管其与阿片类安全性评估相关。在这里，我们评估了三种新型阿片类药物的呼吸抑制和抗伤害性作用，并将这些测量结果与其体外efficacy.Experimental ApproachResponsibility相关。使用热板试验测量抗伤害感受。吗啡、奥利色定和噻奈普汀经腹腔给药，而美沙酮、羟考酮和SR-17018经口给药。在HEK 293细胞中使用BRET检测测定受体激活和arrestin-3募集。Key ResultsAcross the dose range examined，所有研究的阿片类药物均以剂量依赖性方式抑制呼吸，在最高剂量下具有相似的作用，与吗啡、羟考酮、美沙酮和SR-17018相比，噻奈普汀和奥利西定显示出作用持续时间缩短。当以诱导相似呼吸抑制的剂量给药时，所有阿片类药物均诱导相似的抗伤害感受，噻奈普汀和奥利色定再次显示作用持续时间缩短。这些数据与体外激动剂活性的测试compounds. ConclusionandImplicationsIn除了提供有效的抗伤害性，新的阿片类药物，oliceridine，噻奈普汀和SR-17018抑制雄性小鼠的呼吸。然而，这些新型阿片类药物之间的不同效力和作用动力学可能与其在不同临床环境中的治疗应用有关。
Background and PurposeOpioid‐induced respiratory depression limits the use of μ‐opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The relative potential of different opioid agonists to induce respiratory depression at doses exceeding those producing analgesia is understudied despite its relevance to assessments of opioid safety. Here we evaluated the respiratory depressant and anti‐nociceptive effects of three novel opioids and relate these measurements to their in vitro efficacy.Experimental ApproachRespiration was measured in awake, freely moving male CD‐1 mice using whole body plethysmography. Anti‐nociception was measured using the hot plate test. Morphine, oliceridine and tianeptine were administered intraperitoneally, whereas methadone, oxycodone and SR‐17018 were administered orally. Receptor activation and arrestin‐3 recruitment were measured in HEK293 cells using BRET assays.Key ResultsAcross the dose ranges examined, all opioids studied depressed respiration in a dose‐dependent manner, with similar effects at the highest doses, and with tianeptine and oliceridine showing reduced duration of effect, when compared with morphine, oxycodone, methadone and SR‐17018. When administered at doses that induced similar respiratory depression, all opioids induced similar anti‐nociception, with tianeptine and oliceridine again showing reduced duration of effect. These data were consistent with the in vitro agonist activity of the tested compounds.Conclusion and ImplicationsIn addition to providing effective anti‐nociception, the novel opioids, oliceridine, tianeptine and SR‐17018 depress respiration in male mice. However, the different potencies and kinetics of effect between these novel opioids may be relevant to their therapeutic application in different clinical settings.