Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors
Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors
复制标题
DOI：
10.1038/npp.2016.38
复制
发表时间：
2016-08-01
影响因子：
7.6
通讯作者：
Lucki, Irwin
中科院分区：
文献类型：
--
作者：
Falcon, Edgardo;Browne, Caroline A.;Lucki, Irwin
先前的研究已经确定了丁丙诺啡（BPN）的潜在抗抑郁作用，丁丙诺啡是一种对μ阿片受体（MORs）和κ阿片受体（KORs）具有高亲和力的药物，对δ阿片受体（DOR）和阿片受体样1（ORL-I）受体具有一定亲和力。因此，这些研究检查了哪些阿片受体参与了BPN对抗抑郁药物敏感的动物行为试验的影响。在强迫游泳试验（FST）中，使用个体阿片受体基因缺失或受体药理学阻断后的小鼠检测BPN的急性作用。为了评估BPN对慢性应激的影响，将单独的小鼠组暴露于不可预测的慢性轻度应激（UCMS）3周，并用BPN处理至少7天，然后进行行为评估并随后测量多个脑区域中的Oprkl、Oprml和Pdyn mRNA表达。BPN并没有减少KOR缺失小鼠的不动性，也没有减少norbinaltorphimine预处理后的不动性，尽管地昔帕明仍然有效。相反，BPN降低了莫尔和DOR敲除小鼠和ORL-1拮抗剂JTC-801预处理小鼠的不动性。UCMS降低蔗糖偏好，减少在亮/暗箱的亮侧的时间，增加FST中的不动性，并诱导额皮质和纹状体中Oprkl、Oprml和PDYN mRNA表达的区域特异性改变。所有这些变化在BPN治疗后均正常化。在小鼠抗抑郁药物敏感试验中，KOR被确定为介导BPN效应的关键参与者。这些研究支持进一步开发BPN作为一种新型抗抑郁药。
Previous studies have identified potential antidepressant effects of buprenorphine (BPN), a drug with high affinity for mu opioid receptor (MORs) and kappa opioid receptors (KORs) and some affinity at delta opioid receptor (DOR) and opioid receptor-like 1 (ORL-I) receptors. Therefore, these studies examined which opioid receptors were involved in BPN's effects on animal behavior tests sensitive to antidepressant drugs. The acute effects of BPN were tested in the forced swim test (FST) using mice with genetic deletion of individual opioid receptors or after pharmacological blockade of receptors. For evaluating the effects of BPN on chronic stress, separate groups of mice were exposed to unpredictable chronic mild stress (UCMS) for 3 weeks and treated with BPN for at least 7 days before behavioral assessment and subsequent measurement of Oprkl, Oprml, and Pdyn mRNA expression in multiple brain regions. BPN did not reduce immobility in mice with KOR deletion or after pretreatment with norbinaltorphimine, even though desipramine remained effective. In contrast, BPN reduced immobility in MOR and DOR knockout mice and in mice pretreated with the ORL-I antagonist JTC-801. UCMS reduced sucrose preference, decreased time in the light side of the light/ dark box, increased immobility in the FST and induced region-specific alterations in Oprkl, Oprml, and PDYN mRNA expression in the frontal cortex and striatum. All of these changes were normalized following BPN treatment. The KOR was identified as a key player mediating the effects of BPN in tests sensitive to antidepressant drugs in mice. These studies support further development of BPN as a novel antidepressant.