L-cysteine ethyl ester prevents and reverses acquired physical dependence on morphine in male Sprague Dawley rats.
L-cysteine ethyl ester prevents and reverses acquired physical dependence on morphine in male Sprague Dawley rats.
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DOI：
10.3389/fphar.2023.1303207
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发表时间：
2023
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
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吗啡成瘾/依赖的分子机制可能源于阿片类药物通过抑制兴奋性氨基酸转运体3(EAA3)而减少L半胱氨酸向神经元的转运。本研究的目的是确定细胞渗透剂L-硫醇酯、L-半胱氨酸乙酯(L-半胱氨酸乙酯)合用是否能减少雄性SD大鼠对吗啡的身体依赖。注射阿片受体拮抗剂盐酸纳洛酮(NLX；1.5 mg/kg，ip)可引起大鼠明显的戒断现象。大鼠皮下注射吗啡(150 mg/kg)36h，同时经渗透压微量泵持续滴注生理盐水(20μL/h，iv)36h。戒断现象包括湿狗抖动、跳跃、直立、前爪舔、360度转圈、扭动、呼吸暂停、心血管(升压和心动过速)反应、体温过低和体重减轻。静脉注射L-CySee(20.8μ/kg/h，iv)36h后，大鼠戒断症状显著减少。皮下注射吗啡(150 mg/kg)48h后，NLX可诱发显著的戒断症状。然而，在吗啡(150 mg/kg连续48小时)处理的大鼠开始36小时静脉注射L-胱氨酸(20.8μμ/kg/h，IV)后，催促戒断症状明显减少。在与前面描述的研究类似的研究中，L-半胱氨酸和L-丝氨酸乙酯(均为20.8 mol/kg/h，IV)都没有L-Cysee的作用。这项研究表明，1)L-Cysee可减轻雄性大鼠对吗啡的身体依赖；2)预先给药L-CySee可逆转吗啡依赖，这很可能是通过脑细胞内的作用实现的。缺乏L-丝氨酸乙酯(氧原子而不是硫原子)的作用，强烈暗示硫醇生物化学在L-Cysee的作用中。因此，L-赛斯及其类似物可能是一种新的治疗方法，可以改善人类对阿片类药物的身体依赖。
The molecular mechanisms underlying the acquisition of addiction/dependence on morphine may result from the ability of the opioid to diminish the transport of L-cysteine into neurons via inhibition of excitatory amino acid transporter 3 (EAA3). The objective of this study was to determine whether the co-administration of the cell-penetrant L-thiol ester, L-cysteine ethyl ester (L-CYSee), would reduce physical dependence on morphine in male Sprague Dawley rats. Injection of the opioid-receptor antagonist, naloxone HCl (NLX; 1.5 mg/kg, IP), elicited pronounced withdrawal phenomena in rats which received a subcutaneous depot of morphine (150 mg/kg) for 36 h and were receiving a continuous infusion of saline (20 μL/h, IV) via osmotic minipumps for the same 36 h period. The withdrawal phenomena included wet-dog shakes, jumping, rearing, fore-paw licking, 360° circling, writhing, apneas, cardiovascular (pressor and tachycardia) responses, hypothermia, and body weight loss. NLX elicited substantially reduced withdrawal syndrome in rats that received an infusion of L-CYSee (20.8 μmol/kg/h, IV) for 36 h. NLX precipitated a marked withdrawal syndrome in rats that had received subcutaneous depots of morphine (150 mg/kg) for 48 h) and a co-infusion of vehicle. However, the NLX-precipitated withdrawal signs were markedly reduced in morphine (150 mg/kg for 48 h)-treated rats that began receiving an infusion of L-CYSee (20.8 μmol/kg/h, IV) at 36 h. In similar studies to those described previously, neither L-cysteine nor L-serine ethyl ester (both at 20.8 μmol/kg/h, IV) mimicked the effects of L-CYSee. This study demonstrates that 1) L-CYSee attenuates the development of physical dependence on morphine in male rats and 2) prior administration of L-CYSee reverses morphine dependence, most likely by intracellular actions within the brain. The lack of the effect of L-serine ethyl ester (oxygen atom instead of sulfur atom) strongly implicates thiol biochemistry in the efficacy of L-CYSee. Accordingly, L-CYSee and analogs may be a novel class of therapeutics that ameliorate the development of physical dependence on opioids in humans.
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影响因子：
4.2
作者：
Nielsen, David A.;Kreek, Mary Jeanne
通讯作者：
Kreek, Mary Jeanne
影响因子：
6.1
作者：
Brognara, Fernanda;Martins Dias, Daniel P.;Salgado, Helio C.
通讯作者：
Salgado, Helio C.
影响因子：
6.1
作者：
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Cicero, Theodore J.
影响因子：
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作者：
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KV1.2钾通道的细胞外氧化还原敏感性。
影响因子：
4.6
作者：
Baronas VA;Yang RY;Kurata HT
通讯作者：
Kurata HT