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.

项目概要 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，造成了毁灭性的后果 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、更好的 OUD 预防和治疗策略。我们团队的目标 是开发可以预防或对抗阿片类药物滥用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测定法来筛选可能减少 阿片类药物自我给药。用这种范式进行药物筛选揭示了最有效的分子之一 抑制阿片类药物寻求的是非那雄胺（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)，该酶催化合成中的限速步骤 几种神经类固醇（包括四氢孕酮和 GABA-A 受体的其他变构调节剂），以及 如睾酮和皮质酮的代谢。然而，类固醇谱的具体变化 FIN 是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，Bortolato 集团 研究了 FIN 在精神疾病啮齿动物模型中的行为影响，发现该药物 减少冲动行为和自我滥用其他药物的严重程度。这些研究有 还表明FIN的作用与多巴胺信号传导有关，但不影响阿片受体的功能。 因此，我们的初步数据表明 FIN 不会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 关于我们在斑马鱼模型上的发现的转化能力的数据并确定其机制 由此 FIN 减少阿片类药物的自我给药。该提案的两个目标是：1）使用经过充分验证的 大鼠模型测试阿片类药物的自我给药是否被 FIN 逆转或阻止，并研究潜在的性别 与这些影响相关的差异； 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 拟议的研究将导致未来的研究验证 FIN 对阿片类药物自我治疗多个阶段的影响 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 改变阿片类药物的奖励效果。鉴于 FIN 已在患者中使用超过 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使用的临床试验 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可能性而不干扰 这些药物的镇痛特性。