D-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception.
D-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception.
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DOI：
10.1038/s41598-021-89455-2
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发表时间：
2021-05-11
影响因子：
4.6
通讯作者：
Lewis SJ
中科院分区：
文献类型：
--
作者：
Gaston B;Baby SM;May WJ;Young AP;Grossfield A;Bates JN;Seckler JM;Wilson CG;Lewis SJ
我们已经确定硫酯可以逆转阿片类药物对呼吸的负面影响，同时又不影响抗痛觉性。在这里，我们报道了d-胱氨酸二乙酯（d-胱氨酸diEE）或d-胱氨酸二甲酯（d-胱氨酸diME）对吗啡诱导的自由运动大鼠通气、动脉血气化学、a -梯度（肺气体交换指数）和抗疼痛的影响。注射吗啡（10mg /kg，静脉注射）会对呼吸产生负面影响（如潮气量降低、微小通气量降低、吸气流量峰值降低、吸气动力减弱）。随后注射d-胱氨酸diEE （500 μmol/kg， IV）可立即持续逆转吗啡的这些作用。注射吗啡（10mg /kg， IV）也引起动脉血pH、pO2和sO2的显著降低，同时pCO2显著升高（均表明通气驱动降低）和a -a梯度（肺内通气灌注不匹配）。d-胱氨酸diME （500 μmol/kg， IV）可以立即和持续地逆转吗啡的这些作用。最后，d-胱氨酸diEE延长吗啡（5和10 mg/kg， IV）抗避孕的持续时间。d-胱氨酸diEE和d-胱氨酸diME可能是临床有用的药物，可以有效逆转吗啡对呼吸和肺部气体交换的负面影响，同时促进抗避孕作用。我们的研究表明，d-胱氨酸硫酯能够不同地调节介导吗啡诱导的通气抑制的细胞内信号级联，而不是那些介导吗啡诱导的抗痛觉和镇静的细胞内信号级联。
We have identified thiolesters that reverse the negative effects of opioids on breathing without compromising antinociception. Here we report the effects of d-cystine diethyl ester (d-cystine diEE) or d-cystine dimethyl ester (d-cystine diME) on morphine-induced changes in ventilation, arterial-blood gas chemistry, A-a gradient (index of gas-exchange in the lungs) and antinociception in freely moving rats. Injection of morphine (10 mg/kg, IV) elicited negative effects on breathing (e.g., depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive). Subsequent injection of d-cystine diEE (500 μmol/kg, IV) elicited an immediate and sustained reversal of these effects of morphine. Injection of morphine (10 mg/kg, IV) also elicited pronounced decreases in arterial blood pH, pO2 and sO2 accompanied by pronounced increases in pCO2 (all indicative of a decrease in ventilatory drive) and A-a gradient (mismatch in ventilation-perfusion in the lungs). These effects of morphine were reversed in an immediate and sustained fashion by d-cystine diME (500 μmol/kg, IV). Finally, the duration of morphine (5 and 10 mg/kg, IV) antinociception was augmented by d-cystine diEE. d-cystine diEE and d-cystine diME may be clinically useful agents that can effectively reverse the negative effects of morphine on breathing and gas-exchange in the lungs while promoting antinociception. Our study suggests that the d-cystine thiolesters are able to differentially modulate the intracellular signaling cascades that mediate morphine-induced ventilatory depression as opposed to those that mediate morphine-induced antinociception and sedation.
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影响因子：
8.8
作者：
Dahan, Albert;van der Schrier, Rutger;Niesters, Marieke
通讯作者：
Niesters, Marieke
影响因子：
3.3
作者：
Gaston, Benjamin;May, Walter J.;Lewis, Stephen J.
通讯作者：
Lewis, Stephen J.
影响因子：
1.7
作者：
Chapman, Colin D.;Dono, Lindsey M.;Currie, Paul J.
通讯作者：
Currie, Paul J.
影响因子：
3.3
作者：
EPSTEIN, RA;EPSTEIN, MAF;MELLINS, RB
通讯作者：
MELLINS, RB
DOI：
10.1002/prca.201600004
发表时间：
2016-12
期刊：
Proteomics. Clinical applications
影响因子：
--
作者：
Henderson M;Rice B;Sebastian A;Sullivan PG;King C;Robinson RA;Reed TT
通讯作者：
Reed TT