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

基本信息

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
项目类别：
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

项目摘要

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为了遏制这种流行病，美国国立卫生研究院最近发布了 HEAL 倡议。促进开发新的、更好的 OUD 预防和治疗策略是我们团队的目标。旨在开发可预防或对抗阿片类药物滥用的新型非阿片类药物。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使用这种范例进行的阿片类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 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），以及然而，睾酮和皮质酮的代谢存在类固醇谱的具体变化。 FIN 是否会减少阿片类药物的自我给药在过去几年中仍不清楚。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本申请中提出的探索性合作研究旨在获得关键模型。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因此，FIN 减少了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药物。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效应相关的差异；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。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鉴于 FIN 已在患者中使用超过 25 年，FIN 改变了阿片类药物的奖励效果。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。