Exploring steroid-based therapies to reduce opioid abuse

探索基于类固醇的疗法以减少阿片类药物滥用

• 批准号: 9916192
• 负责人: Marco Bortolato
• 金额: $ 22.88万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916192
• 关键词: Adjuvant; Adverse event; Affect; Allopregnanolone; Alopecia; American; Analgesics; Animal Model; Benign Prostatic Hypertrophy; Biological Assay; Brain; Buprenorphine; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Trials; Cocaine; Complement; Corticosterone; Criminal Justice; Data; Dependence; Development; Dopamine; Drug Screening; Drug Targeting; Economic Burden; Enzymes; Epidemic; Exhibits; Female; Finasteride; Fishes; Future; GABA Modulators; GABA-A Receptor; Goals; Health Care Costs; Hydrocodone; Impulsive Behavior; Intervention; Investigation; Lead; Libraries; Male Pattern Baldness; Mediating; Mental disorders; Metabolism; Methadone; Modeling; Molecular; Motor; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Receptor; Opioid agonist; Opioid replacement therapy; Overdose; Oxidoreductase; Patients; Pharmaceutical Preparations; Pilot Projects; Prevention therapy; Productivity; Property; Prostatic; Public Health; Rattus; Rewards; Risk; Rodent Model; Safety; Self Administration; Sensory; Severities; Sex Differences; Signal Transduction; Steroids; Testing; Testosterone; Therapeutic Effect; United States National Institutes of Health; Zebrafish; addiction; base; behavioral study; chronic neuropathic pain; cost effective; drug discovery; drug of abuse; drug seeking behavior; healing; male; neurochemistry; neurosteroids; non-opioid analgesic; novel; opioid abuse; opioid misuse; opioid overdose; opioid therapy; opioid use disorder; prescription opioid; prescription opioid misuse; prevent; public health emergency; receptor; response; screening; socioeconomics; therapeutic evaluation

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.

项目摘要 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， 社会经济影响。为了遏制这种流行病，NIH最近发布了HEAL倡议 促进开发新的和更好的OUD预防和治疗策略。我们团队的目标 开发新型非阿片类药物，以防止或对抗阿片类药物的滥用倾向。为此中央 彼得森实验室最近开发了一种高通量的斑马鱼检测方法，用于筛选可能降低 阿片类药物自我给药。用这种模式进行的药物筛选显示， 抑制阿片类药物寻求的药物是芬替尼（FIN），这是一种批准用于临床的药物，具有良好的安全性， 耐受性FIN抑制5α-还原酶（5αR），该酶催化合成 几种神经类固醇（包括别孕烯醇酮和GABA-A受体的其他变构调节剂），以及 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自我给药仍不清楚。在过去的几年里，Bortolato集团 研究了FIN在啮齿动物精神障碍模型中的行为效应，发现这种药物 减少冲动行为和自我施用其他药物滥用的严重性。这些研究 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，我们的初步数据表明，FIN不干扰阿片类药物在大鼠中的镇痛特性。 模型本申请中提出的探索性合作研究旨在获得关键的 数据的翻译能力，我们的发现对斑马鱼模型，并确定机制 从而FIN减少阿片类药物的自我给药。该提案的两个目标是：1）使用经过验证的 大鼠模型，以测试阿片类自我给药是否被FIN逆转或阻止，并研究潜在的性别 与这些影响有关的差异;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对阿片类自我给药的影响。结果 拟议的研究将导致未来的研究，以验证FIN对阿片类药物自我的多个阶段的影响， 给药（也在慢性和神经性疼痛的大鼠模型中）和基于类固醇的机制， FIN改变了阿片类药物的奖励作用。鉴于FIN已用于患者超过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对其使用的临床试验 作为阿片类止痛药的辅助治疗，可减少阿片类药物滥用的可能性，而不干扰 这些药物的镇痛作用。