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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.

项目总结