1 Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Santa Maria, Santa Maria, Brasil.
2 Departamento de Patologia, Universidade Federal de Santa Maria, Santa Maria, Brazil.
J Psychopharmacol. 2017 Sep;31(9):1250-1262. doi: 10.1177/0269881117724353. Epub 2017 Aug 31.
Animal and clinical researches indicate that the opioid system exerts a crucial role in the etiology of mood disorders and is a target for intervention in depression treatment. This study investigated the contribution of the opioid system to the antidepressant-like action of acute or repeated m-trifluoromethyl-diphenyl diselenide administration to Swiss mice. m-Trifluoromethyl-diphenyl diselenide (50 mg/kg, intragastric) produced an antidepressant-like action in the forced swimming test from 30 min to 24 h after treatment. This effect was blocked by the µ and δ-opioid receptor antagonists, naloxonazine (10 mg/kg, intraperitoneally) and naltrindole (3 mg/kg, intraperitoneally), and it was potentiated by a κ-opioid receptor antagonist, norbinaltrophimine (1 mg/kg, subcutaneously ). Combined treatment with subeffective doses of m-trifluoromethyl-diphenyl diselenide (10 mg/kg, intragastric) and morphine (1 mg/kg, subcutaneously) resulted in a synergistic antidepressant-like effect. The opioid system contribution to the m-trifluoromethyl-diphenyl diselenide antidepressant-like action was also demonstrated in the modified tail suspension test, decreasing mouse immobility and swinging time and increasing curling time, results similar to those observed using morphine, a positive control. Treatment with m-trifluoromethyl-diphenyl diselenide induced neither tolerance to the antidepressant-like action nor physical signs of withdrawal, which could be associated with the fact that m-trifluoromethyl-diphenyl diselenide did not change the mouse cortical and hippocampal glutamate uptake and release. m-Trifluoromethyl-diphenyl diselenide treatments altered neither locomotor nor toxicological parameters in mice. These findings demonstrate that m-trifluoromethyl-diphenyl diselenide elicited an antidepressant-like action by direct or indirect μ and δ-opioid receptor activation and the κ-opioid receptor blockade, without inducing tolerance, physical signs of withdrawal and toxicity.
动物和临床研究表明，阿片系统在心境障碍的发病机制中起着至关重要的作用，是抑郁症治疗干预的靶点。本研究探讨了阿片系统对急性或重复 m-三氟甲基-二苯二硒醚给药对瑞士小鼠抗抑郁作用的贡献。m-三氟甲基-二苯二硒醚（50mg/kg，灌胃）在处理后 30 分钟至 24 小时的强迫游泳试验中产生抗抑郁作用。这种作用被 μ 和 δ-阿片受体拮抗剂纳洛酮嗪（10mg/kg，腹腔内）和纳曲吲哚（3mg/kg，腹腔内）阻断，并被 κ-阿片受体拮抗剂诺比那特罗米辛（1mg/kg，皮下）增强。m-三氟甲基-二苯二硒醚（10mg/kg，灌胃）和吗啡（1mg/kg，皮下）的亚效剂量联合治疗产生协同抗抑郁作用。阿片系统对 m-三氟甲基-二苯二硒醚抗抑郁作用的贡献也在改良的悬尾试验中得到了证明，减少了小鼠的不动和摆动时间，增加了卷曲时间，结果与阳性对照吗啡相似。m-三氟甲基-二苯二硒醚治疗既没有诱导抗抑郁作用的耐受，也没有诱导戒断的躯体体征，这可能与 m-三氟甲基-二苯二硒醚不改变小鼠皮质和海马谷氨酸摄取和释放有关。m-三氟甲基-二苯二硒醚治疗既没有改变小鼠的运动能力，也没有改变其毒理学参数。这些发现表明，m-三氟甲基-二苯二硒醚通过直接或间接激活 μ 和 δ-阿片受体和阻断 κ-阿片受体产生抗抑郁作用，而不诱导耐受、躯体戒断体征和毒性。
