The ventilatory depressant actions but not the antinociceptive effects of morphine are blunted in rats receiving intravenous infusion of L-cysteine ethyl ester.
The ventilatory depressant actions but not the antinociceptive effects of morphine are blunted in rats receiving intravenous infusion of L-cysteine ethyl ester.
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DOI：
10.1016/j.biopha.2022.113939
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发表时间：
2022-12
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该研究表明，向成年雄性Sprague-Dawley大鼠静脉内输注细胞渗透剂硫羟酸酯，L-半胱氨酸乙酯（L-CYSee）引起（a）呼吸频率、呼气时间、潮气量、每分钟通气量或呼气驱动力的微小改变，但吸气时间、吸气末和呼气末停顿、吸气和呼气峰流量、EF 50、松弛时间、呼吸暂停、吸气驱动和非正常呼吸指数，（B）动脉血气（ABG）化学（pH、pCO 2、pO 2、SO2）和肺泡-动脉（A-a）梯度（肺泡气体交换指数）的最小变化，和（c）抗伤害感受（甩尾潜伏期）的最小变化。随后注射吗啡（10 mg/kg，IV）在接受L-CYSee的大鼠中引起对上述参数、ABG化学和A-a梯度的明显较小的影响，而吗啡抗伤害感受未受损。输注L-半胱氨酸或L-丝氨酸乙酯（氧而不是硫部分）不影响吗啡对ABG化学或A-a梯度的作用。L-CYSee（250 μmol/kg，IV）注射吗啡15 min后，大鼠的镇痛参数发生显著变化。我们的发现表明（a）L-CYSee在驱动通气的神经元中起作用，（B）L-CYSee逆转吗啡对通气、ABG化学和A-a梯度的不利作用可能是通过调节由吗啡激活的细胞内信号传导途径，而不是通过阿片受体的直接拮抗作用，因为L-CYSee不减少吗啡抗伤害感受，和（c）L-CYSee的巯基部分对功效至关重要，（d）L-CYSee向S-亚硝基化形式的细胞内转化可能是其作用机制的一部分。
This study demonstrates that intravenous infusion of the cell-penetrant thiol ester, L-cysteine ethyl ester (L-CYSee), to adult male Sprague-Dawley rats elicited (a) minor alterations in frequency of breathing, expiratory time, tidal volume, minute ventilation, or expiratory drive but pronounced changes in inspiratory time, end-inspiratory and expiratory pauses, peak inspiratory and expiratory flows, EF50, relaxation time, apneic pause, inspiratory drive and non-eupneic breathing index, (b) minimal changes in arterial blood-gas (ABG) chemistry (pH, pCO2, pO2, SO2) and Alveolar-arterial (A-a) gradient (index of alveolar gas exchange), and (c) minimal changes in antinociception (tail-flick latency). Subsequent injection of morphine (10 mg/kg, IV) elicited markedly smaller effects on the above parameters, ABG chemistry, and A-a gradient in rats receiving L-CYSee, whereas morphine antinociception was not impaired. Infusions of L-cysteine or L-serine ethyl ester (oxygen rather than sulfur moiety), did not affect morphine actions on ABG chemistry or A-a gradient. L-CYSee (250 μmol/kg, IV) injection elicited dramatic changes in ventilatory parameters given 15 min after injection of morphine in rats receiving L-CYSee. Our findings suggest that (a) L-CYSee acts in neurons that drive ventilation, (b) L-CYSee reversal of the adverse actions of morphine on ventilation, ABG chemistry and A-a gradient may be via modulation of intracellular signaling pathways activated by morphine rather than by direct antagonism of opioid receptors since morphine antinociception was not diminished by L-CYSee, and (c) the thiol moiety of L-CYSee is vital to efficacy, (d) intracellular conversion of L-CYSee to an S-nitrosylated form may be part of its mechanism of action.
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