The novel μ-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception.
The novel μ-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception.
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DOI：
10.1111/bph.14224
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发表时间：
2018-07
影响因子：
7.3
通讯作者：
Henderson G
中科院分区：
文献类型：
--
作者：
Hill R;Disney A;Conibear A;Sutcliffe K;Dewey W;Husbands S;Bailey C;Kelly E;Henderson G
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，并且不具有吗啡等经典 μ 受体配体特有的呼吸抑制作用。我们重新检查了 PZM21 的信号传导谱及其抑制呼吸的能力。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。 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。每天重复施用 PZM21（每天两次，剂量为 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没有产生耐受。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来说是一种低效 μ 受体激动剂。与之前的报告相反，PZM21 抑制呼吸的方式类似于经典阿片受体激动剂吗啡。
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. 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. 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. 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.
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影响因子：
7.3
作者：
Winpenny, David;Clark, Mellissa;Cawkill, Darren
通讯作者：
Cawkill, Darren
DOI：
10.1038/npp.2015.201
发表时间：
2016-02
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
--
作者：
Hill R;Lyndon A;Withey S;Roberts J;Kershaw Y;MacLachlan J;Lingford-Hughes A;Kelly E;Bailey C;Hickman M;Henderson G
通讯作者：
Henderson G
影响因子：
64.5
作者：
Schmid CL;Kennedy NM;Ross NC;Lovell KM;Yue Z;Morgenweck J;Cameron MD;Bannister TD;Bohn LM
通讯作者：
Bohn LM
影响因子：
64.8
作者：
Matthes, HWD;Maldonado, R;Kieffer, BL
通讯作者：
Kieffer, BL
DOI：
10.1124/jpet.116.238329
发表时间：
2017-04-01
影响因子：
3.5
作者：
Withey, Sarah L.;Hill, Rob;Henderson, Graeme
通讯作者：
Henderson, Graeme