Exploring steroid-based therapies to reduce opioid abuse

项目总结 阿片类药物滥用和依赖已成为美国最大的公共卫生危机之一，具有毁灭性 社会经济影响。在试图遏制这种流行病的过程中，美国国立卫生研究院最近发布了治愈计划 促进发展新的和更好的预防和治疗策略。我们团队的目标是 是开发可防止或对抗阿片类药物滥用责任的新型非阿片类药物。为此， 彼得森实验室最近开发了一种高通量斑马鱼检测方法，以筛选可能会降低 阿片类药物自我给药。用这种模式进行药物筛选发现，最有效的分子之一 为了抑制阿片类药物的寻找是非那雄胺(FIN)，一种被批准用于临床的药物，具有良好的安全性和 耐受性。FIN抑制5α-还原酶(5αR)，该酶催化合成 一些神经类固醇(包括别孕酮和其他GABA-A受体的变构调节剂)也是如此 就像睾丸激素和皮质酮的新陈代谢一样。然而，类固醇特征的具体变化 FIN如何减少阿片类药物的自我给药仍不清楚。在过去的几年里，博尔托拉托集团 研究了FIN对精神障碍啮齿动物模型的行为影响，发现这种药物 减少其他滥用药物的冲动行为和自我管理的严重程度。这些研究已经 研究还表明，FIN的作用与多巴胺信号有关，但不影响阿片受体的功能。 因此，我们的初步数据显示，FIN不干扰阿片类药物在大鼠体内的镇痛特性 模特们。本申请中提出的探索性协作研究旨在获得关键的 关于我们在斑马鱼模型上的发现的翻译能力的数据，并确定其机制 从而减少阿片类药物的自我给药。该提案的两个目标将：1)使用经过充分验证的 建立大鼠模型，测试FIN是否逆转或阻止阿片类药物的自我给药，并研究潜在的性行为 与这些影响相关的差异；以及2)使用高通量斑马鱼模型来识别哪些类固醇 (5αR的底物和产物)负责FIN对阿片类药物自我给药的影响。结果是 建议的研究将导致未来的研究，以验证FIN对阿片类药物自身多个阶段的影响 给药(在慢性和神经病理性疼痛的大鼠模型中也是如此)和基于类固醇的机制 FIN可以改变阿片类药物的奖赏效应。鉴于FIN已经在患者身上使用了超过25年 并且具有非常好的耐受性和安全性，这些研究可能会迅速导致其临床试验 作为阿片类止痛药的辅助治疗，可以减少阿片类药物滥用的责任，而不会干扰 这些药物的止痛特性。

PROJECT SUMMARY Opioid misuse and dependence have become one of the largest public health crises in the US, with devastating socio-economic repercussions. In the attempt to curb this epidemic, NIH has recently issued the HEAL initiative to promote the development of novel and better strategies for OUD prevention and therapy. The goal of our team is to develop novel non-opioid drugs that may prevent or counter the abuse liability of opioids. To this end, the Peterson lab has recently developed a high-throughput zebrafish assay to screen for drugs that may reduce opioid self-administration. Drug screening with this paradigm revealed that one of the most effective molecules to suppress opioid seeking was finasteride (FIN), a drug approved for clinical use with good safety and tolerability. FIN inhibits 5α-reductase (5αR), the enzyme catalyzing the rate-limiting step in the synthesis of several neurosteroids (including allopregnanolone and other allosteric modulators of GABA-A receptors), as well as in the metabolism of testosterone and corticosterone. However, the specific changes in steroid profiles whereby FIN reduces opioid self-administration remain unclear. Over the past few years, the Bortolato group has studied the behavioral effects of FIN in rodent models of psychiatric disorders and found that this drug reduces the severity of impulsive behaviors and self-administration of other drugs of abuse. These studies have also shown that FIN’s effects are related to dopamine signaling, but do not affect the function of opioid receptors. Accordingly, our preliminary data show that FIN does not interfere with the analgesic properties of opioids in rat models. The exploratory collaborative studies proposed in this application are aimed at obtaining critical data on the translational power of our discoveries on the zebrafish model and ascertain the mechanisms whereby FIN reduces opioid self-administration. The two aims of this proposal will: 1) use a well-validated rat model to test whether opioid self-administration is reversed or prevented by FIN, and study potential sex differences in relation to these effects; and 2) use the high-throughput zebrafish model to identify which steroids (substrates and products of 5αR) are responsible for the effects of FIN on opioid self-administration. The results of the proposed studies will lead to future studies to validate the effects of FIN on multiple stages of opioid self- administration (also in rat models of chronic and neuropathic pain) and the steroid-based mechanisms whereby FIN modifies the rewarding effects of opioids. Given that FIN has been used in patients for more than 25 years and has a very good tolerability and safety profile, these studies may rapidly lead to clinical trials on its use as an adjunct treatment to opioid pain-killers that may reduce opioid abuse liability without interfering with the analgesic properties of these drugs.