<br>新型 μ-阿片受体激动剂 PZM21 可抑制呼吸并诱导对镇痛的耐受性。,British Journal of Pharmacology

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新型 μ-阿片受体激动剂 PZM21 可抑制呼吸并诱导对镇痛的耐受性。
British Journal of Pharmacology ( IF 6.8 ) Pub Date : 2018-05-14 , DOI: 10.1111/bph.14224
Rob Hill ₁ , Alex Disney ₂ , Alex Conibear ₁ , Katy Sutcliffe ₁ , William Dewey ₃ , Stephen Husbands ₂ , Chris Bailey ₂ , Eamonn Kelly ₁ , Graeme Henderson ₁

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背景和用途 PZM21 是一种新型 μ-阿片受体配体，据报道可诱导最小程度的抑制蛋白募集，并且不具有经典 μ 受体配体（如吗啡）所特有的呼吸抑制作用。我们重新研究了 PZM21 的信号传导特征及其抑制呼吸的能力。实验方法使用 BRET 测定，在表达 μ 受体的 HEK 293 细胞中体外测量 G 蛋白 (Gi) 激活和抑制蛋白 3 易位。通过全身体积描记法测量清醒、自由活动的小鼠的呼吸（速率和潮气量），并通过热板试验测量镇痛作用。主要结果 PZM21 (10-9 - 3 × 10-5 M) 产生浓度依赖性 Gi 激活和抑制蛋白 3 易位。与吗啡和 DAMGO 引起的反应进行比较表明，PZM21 在两种信号传导测定中都是低效激动剂。 PZM21 (10-80 mg·kg-1 ) 以剂量依赖性方式抑制呼吸。呼吸抑制是由于呼吸频率降低而不是潮气量减少造成的。每日重复施用PZM21（每日两次剂量40 mg·kg-1），在3天内对PZM21的抗伤害作用产生完全耐受，但对其呼吸抑制作用不产生耐受。结论和意义这些数据表明，PZM21 对于 G 蛋白和视紫红质抑制蛋白信号传导而言是一种低效 μ 受体激动剂。与之前的报告相反，PZM21 以类似于经典阿片受体激动剂吗啡的方式抑制呼吸。

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The novel μ-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception.

BACKGROUND AND PURPOSE PZM21 is a novel μ-opioid receptor ligand that has been reported to induce minimal arrestin recruitment and be devoid of the respiratory depressant effects characteristic of classical μ receptor ligands such as morphine. We have re-examined the signalling profile of PZM21 and its ability to depress respiration. EXPERIMENTAL APPROACH G protein (Gi ) activation and arrestin-3 translocation were measured in vitro, using BRET assays, in HEK 293 cells expressing μ receptors. Respiration (rate and tidal volume) was measured in awake, freely moving mice by whole-body plethysmography, and antinociception was measured by the hot plate test. KEY RESULTS PZM21 (10-9 - 3 × 10-5 M) produced concentration-dependent Gi activation and arrestin-3 translocation. Comparison with responses evoked by morphine and DAMGO revealed that PZM21 was a low efficacy agonist in both signalling assays. PZM21 (10-80 mg·kg-1 ) depressed respiration in a dose-dependent manner. The respiratory depression was due to a decrease in the rate of breathing not a decrease in tidal volume. On repeated daily administration of PZM21 (twice daily doses of 40 mg·kg-1 ), complete tolerance developed to the antinociceptive effect of PZM21 over 3 days but no tolerance developed to its respiratory depressant effect. CONCLUSION AND IMPLICATIONS These data demonstrate that PZM21 is a low efficacy μ receptor agonist for both G protein and arrestin signalling. Contrary to a previous report, PZM21 depresses respiration in a manner similar to morphine, the classical opioid receptor agonist.

更新日期：2019-11-01

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