Pharmacology and Therapeutics, National University of Ireland, Galway, Ireland.
Alkermes Inc., Waltham, MA, USA.
J Psychopharmacol. 2019 Dec;33(12):1620-1627. doi: 10.1177/0269881119872203. Epub 2019 Sep 12.
The combination of buprenorphine, a partial mu-opioid receptor agonist and a functional kappa-opioid receptor antagonist, with samidorphan, a functional mu-opioid receptor antagonist, is being developed as an adjunct therapy for major depressive disorder, in order to harness the mood-enhancing effects of opioids without unwanted side-effects such as a risk of addiction. Acute and subacute administration of the combination of buprenorphine and samidorphan is effective in reducing forced swim immobility in the Wistar-Kyoto rat, but the chronic effects have not been examined.
The purpose of this study was to assess if chronic (14-day) administration of buprenorphine (0.1 mg/kg, subcutaneous) alone or in combination with samidorphan (0.3 mg/kg, subcutaneous) maintains antidepressant-like activity in the olfactory bulbectomised rat model and the Wistar-Kyoto rat, two models that exhibit ongoing behavioural deficits in tests commonly used to study effects of antidepressants.
Olfactory bulbectomised-induced hyperactivity was attenuated by chronic administration of buprenorphine alone and in combination with samidorphan, to that of sham control activity levels. Neither buprenorphine nor samidorphan altered stress-associated defecation in sham or olfactory bulbectomised rats in the open field. In Wistar-Kyoto rats, buprenorphine alone significantly reduced forced swim immobility and increased locomotor activity three hours post-final dosing. Buprenorphine plus samidorphan significantly reduced forced swim immobility without changing locomotor activity at this time point. Buprenorphine alone also significantly reduced forced swim immobility 24 h post-final dosing.
Chronic treatment of buprenorphine alone or buprenorphine plus samidorphan is effective in reversing behavioural deficits in distinct non-clinical paradigms. These non-clinical results complement the antidepressant effect of this combination observed in clinical studies.
丁丙诺啡（一种部分μ-阿片受体激动剂和功能性κ-阿片受体拮抗剂）与萨米多福（一种功能性μ-阿片受体拮抗剂）联合使用，正在被开发为治疗重度抑郁症的辅助治疗方法，目的是利用阿片类药物的情绪增强作用，而没有成瘾等不良副作用。丁丙诺啡和萨米多福联合使用的急性和亚急性给药在减少 Wistar-Kyoto 大鼠的强迫游泳不动方面是有效的，但慢性作用尚未被研究。
本研究的目的是评估丁丙诺啡（0.1mg/kg，皮下）单独或与萨米多福（0.3mg/kg，皮下）联合慢性（14 天）给药是否能维持在嗅球切除术大鼠模型和 Wistar-Kyoto 大鼠中的抗抑郁样活性，这两种模型在常用于研究抗抑郁药作用的测试中表现出持续的行为缺陷。
嗅球切除术引起的过度活跃被丁丙诺啡单独和联合萨米多福的慢性给药所减弱，达到假手术对照活动水平。丁丙诺啡和萨米多福均未改变假手术或嗅球切除术大鼠在开放场中的应激相关排便。在 Wistar-Kyoto 大鼠中，丁丙诺啡单独给药在最后一次给药后 3 小时显著减少强迫游泳不动和增加运动活性。丁丙诺啡加萨米多福在该时间点显著减少强迫游泳不动而不改变运动活性。丁丙诺啡单独给药也显著减少了最后一次给药后 24 小时的强迫游泳不动。
丁丙诺啡单独或丁丙诺啡加萨米多福的慢性治疗在逆转不同非临床范式中的行为缺陷方面是有效的。这些非临床结果补充了临床研究中观察到的这种联合的抗抑郁作用。
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