Samuels Benjamin Adam, Nautiyal Katherine M, Kruegel Andrew C, Levinstein Marjorie R, Magalong Valerie M, Gassaway Madalee M, Grinnell Steven G, Han Jaena, Ansonoff Michael A, Pintar John E, Javitch Jonathan A, Sames Dalibor, Hen René
Department of Psychology, Behavioral &Systems Neuroscience, Rutgers, The State University of New Jersey-New Brunswick, Piscataway, NJ, USA.
Department of Psychiatry, Columbia University, and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, NY, USA.
Neuropsychopharmacology. 2017 Sep;42(10):2052-2063. doi: 10.1038/npp.2017.60. Epub 2017 Mar 17.
Depression is a debilitating chronic illness that affects around 350 million people worldwide. Current treatments, such as selective serotonin reuptake inhibitors, are not ideal because only a fraction of patients achieve remission. Tianeptine is an effective antidepressant with a previously unknown mechanism of action. We recently reported that tianeptine is a full agonist at the mu opioid receptor (MOR). Here we demonstrate that the acute and chronic antidepressant-like behavioral effects of tianeptine in mice require MOR. Interestingly, while tianeptine also produces many opiate-like behavioral effects such as analgesia and reward, it does not lead to tolerance or withdrawal. Furthermore, the primary metabolite of tianeptine (MC5), which has a longer half-life, mimics the behavioral effects of tianeptine in a MOR-dependent fashion. These results point to the possibility that MOR and its downstream signaling cascades may be novel targets for antidepressant drug development.
抑郁症是一种使人衰弱的慢性疾病，全球约有3.5亿人受其影响。目前的治疗方法，如选择性5-羟色胺再摄取抑制剂，并不理想，因为只有一小部分患者能实现症状缓解。噻奈普汀是一种有效的抗抑郁药，其作用机制此前尚不明确。我们最近报告称，噻奈普汀是μ阿片受体（MOR）的完全激动剂。在此我们证明，噻奈普汀在小鼠中的急性和慢性抗抑郁样行为效应需要MOR。有趣的是，虽然噻奈普汀也会产生许多类似阿片类药物的行为效应，如镇痛和奖赏，但它不会导致耐受性或戒断反应。此外，噻奈普汀的主要代谢产物（MC5），其半衰期更长，以MOR依赖的方式模拟了噻奈普汀的行为效应。这些结果表明，MOR及其下游信号级联可能是抗抑郁药物开发的新靶点。
