Martins Carolina C, Rosa Suzan G, Recchi Ana M S, Nogueira Cristina W, Zeni Gilson
Laboratory of Synthesis, Reactivity, Pharmacological and Toxicological Evaluation of Organochalcogen Compounds, Department of Biochemistry and Molecular Biology, Center of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS 97105-900, Brazil.
Laboratory of Synthesis, Reactivity, Pharmacological and Toxicological Evaluation of Organochalcogen Compounds, Department of Biochemistry and Molecular Biology, Center of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS 97105-900, Brazil.
Prog Neuropsychopharmacol Biol Psychiatry. 2020 Mar 2;98:109803. doi: 10.1016/j.pnpbp.2019.109803. Epub 2019 Nov 2.
The opioid withdrawal syndrome is defined as a complex phenomenon involving multiple cellular adaptations, which leads to the emergence of aversive physical and affective signs. The m-trifluoromethyl-diphenyl diselenide (m-CF-PhSe) elicits an antidepressant-like effect by modulating the opioid system in different animal models of mood disorders. Notably, repeated exposure to (m-CF-PhSe) developed neither tolerance nor withdrawal signs in mice. The aim of the present study was to investigate whether (m-CF-PhSe) attenuates the physical signs and the depressive-like phenotype during morphine withdrawal through its neuroprotective effects on oxidative stress, the NMDA receptor and the proBDNF/mBDNF signaling in the hippocampus of mice. Adult Swiss mice received saline solution or escalating doses (20-100 mg/kg, sc) of morphine for six days. For the next three days, the animals were treated with canola oil, (m-CF-PhSe) (5 and 10 mg/kg, ig) or methadone (5 mg/kg, sc) whereas morphine injections were discontinued. On day 9, physical withdrawal signs and depressive-like behavior were assessed 30 min after the last administration of (m-CF-PhSe) Although short-term treatment with (m-CF-PhSe) at both doses suppressed the aversive physical and affective signs in morphine withdrawn-mice, the highest dose of (m-CF-PhSe) per se increased the teeth chattering manifestation. The intrinsic antioxidant property of (m-CF-PhSe) modulated oxidative stress, it also restored the NMDA receptor levels in the hippocampus of morphine withdrawn-mice. Besides, (m-CF-PhSe) downregulated the proBDNF/p-75/JNK pro-apoptotic pathway without affecting the mBDNF/TrkB/ERK/CREB pro-survival signaling in the hippocampus of morphine withdrawn-mice. The results show that (m-CF-PhSe) treatment modulated the hippocampal neurotoxic adaptations and abolished the depressive-like phenotype following morphine withdrawal in mice.
阿片类药物戒断综合征被定义为一种涉及多种细胞适应性变化的复杂现象，会导致出现厌恶的身体和情感症状。间三氟甲基二苯基二硒醚（m-CF-PhSe）通过在不同的情绪障碍动物模型中调节阿片系统，引发类似抗抑郁的效果。值得注意的是，在小鼠中重复接触（m-CF-PhSe）既不会产生耐受性，也不会出现戒断症状。本研究的目的是调查（m-CF-PhSe）是否通过对小鼠海马体中的氧化应激、NMDA受体和proBDNF/mBDNF信号传导产生神经保护作用，来减轻吗啡戒断期间的身体症状和抑郁样表型。成年瑞士小鼠连续六天接受生理盐水或递增剂量（20-100mg/kg，皮下注射）的吗啡。在接下来的三天里，动物接受菜籽油、（m-CF-PhSe）（5和10mg/kg，灌胃）或美沙酮（5mg/kg，皮下注射）治疗，同时停止注射吗啡。在第9天，在最后一次给予（m-CF-PhSe）30分钟后评估身体戒断症状和抑郁样行为。虽然两种剂量的（m-CF-PhSe）短期治疗都能抑制吗啡戒断小鼠的厌恶身体和情感症状，但（m-CF-PhSe）的最高剂量本身会增加牙齿打颤的表现。（m-CF-PhSe）的内在抗氧化特性调节氧化应激，还能恢复吗啡戒断小鼠海马体中的NMDA受体水平。此外，（m-CF-PhSe）下调了proBDNF/p-75/JNK促凋亡途径，而不影响吗啡戒断小鼠海马体中的mBDNF/TrkB/ERK/CREB促生存信号传导。结果表明，（m-CF-PhSe）治疗可调节海马体神经毒性适应性变化，并消除小鼠吗啡戒断后的抑郁样表型。
