吗啡通过抑制兴奋性氨基酸转运蛋白3(EAA3)来减少半胱氨酸转运到神经元的能力可能是获得对吗啡的生理和心理依赖性的关键分子机制。这项研究检查了细胞渗透抗氧化剂D-硫醇酯的共同给药,D-半胱氨酸乙酯(D-CYSee),用吗啡,将减少雄性SpragueDawley大鼠对吗啡的身体依赖性。阿片受体拮抗剂的全身给药,纳洛酮(NLX),引出明显的退出迹象(例如,湿狗奶昔,跳跃,rears,循环)在接受皮下吗啡(150mg/kg,SC)36小时,连续静脉输注载体(20μL/h,IV).在接受D-CYSee输注的大鼠中,NLX沉淀的戒断体征减少,但不是D-半胱氨酸,(均为20.8μmol/kg/h,IV)整整36小时。NLX在吗啡(150mg/kg,SC),加连续输注载体(20μL/h,IV)在吗啡治疗的36小时时间点开始。在接受12小时输注D-CYSee的大鼠中,NLX沉淀的戒断体征减少,但不是D-半胱氨酸,(均为20.8μmol/kg/h,IV)在吗啡治疗的36小时时间点开始。这些发现表明,D-CYSee可以减轻雄性SpragueDawley大鼠对吗啡的身体依赖性,并逆转对阿片类药物的依赖性。或者,D-CYSee可以简单地抑制负责NLX沉淀的戒断的过程。尽管如此,D-CYSee和类似物可能是用于治疗阿片样物质使用障碍的新型治疗剂。
The ability of morphine to decrease cysteine transport into neurons by inhibition of excitatory amino acid transporter 3 (EAA3) may be a key molecular mechanism underlying the acquisition of physical and psychological dependence to morphine. This study examined whether co-administration of the cell-penetrant antioxidant D-thiol ester, D-cysteine ethyl ester (D-CYSee), with morphine, would diminish the development of physical dependence to morphine in male Sprague Dawley rats. Systemic administration of the opioid receptor antagonist, naloxone (NLX), elicited pronounced
withdrawal signs (e.g., wet-dog shakes, jumps, rears, circling) in rats that received a subcutaneous depot of morphine (150 mg/kg, SC) for 36 h and continuous intravenous infusion of vehicle (20 μL/h, IV). The NLX-precipitated
withdrawal signs were reduced in rats that received an infusion of D-CYSee, but not D-cysteine, (both at 20.8 μmol/kg/h, IV) for the full 36 h. NLX elicited pronounced
withdrawal signs in rats treated for 48 h with morphine (150 mg/kg, SC), plus continuous infusion of vehicle (20 μL/h, IV) that began at the 36 h timepoint of morphine treatment. The NLX-precipitated
withdrawal signs were reduced in rats that received a 12 h infusion of D-CYSee, but not D-cysteine, (both at 20.8 μmol/kg/h, IV) that began at the 36 h timepoint of morphine treatment. These findings suggest that D-CYSee may attenuate the development of physical dependence to morphine and reverse established dependence to the opioid in male Sprague Dawley rats. Alternatively, D-CYSee may simply suppress the processes responsible for NLX-precipitated
withdrawal. Nonetheless, D-CYSee and analogues may be novel therapeutics for the treatment of opioid use disorders.