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Heroin Addiction: Predicting Vulnerability & Identification of a Novel Treatment

海洛因成瘾：预测脆弱性

基本信息

批准号：
8836994
负责人：
ROBERT LEVENSON
金额：
$ 18.84万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8836994
关键词：
Abstinence Accidents Adult Agonist American Analgesics Behavior Behavioral Model Behavioral Paradigm Binding Brain Carrier Proteins Cause of Death Cell membrane Cessation of life Chronic Complex Dendritic Spines Dependence Development Disease Dopamine D2 Receptor Drug Prescriptions Exhibits Fentanyl Glycoproteins Goals Health Heroin Heroin Dependence Hippocampus (Brain)Human In Vitro Knowledge Lead Lentivirus Vector Link Maintenance Mediator of activation protein Modeling Molecular Morphine Naloxone Neurons New England Occupations Opiate Addiction Opiates Opioid Opioid Receptor Overdose Pain Patients Peptides Pharmaceutical Preparations Pharmacotherapy Plasmid Cloning Vector Play Prefrontal Cortex Prevention Property Protein Secretion Public Health Rattus Regulation Relapse Resources Rewards Risk Role Self-Injurious Behavior Teenagers Testing Therapeutic Intervention Translating Ventilatory Depression Viral Vector Wnt proteins Writing addiction automobile accident chronic pain craving design drug addiction pharmacotherapy drug seeking behavior expectation experience genetic regulatory protein human RIPK1 protein in vitro testing mimetics mu opioid receptors neurogenesis novel novel strategies prescription opioid prevent research study response treatment center

项目摘要

DESCRIPTION (provided by applicant): Addiction to opioid drugs has become a substantial public health problem due to the large number of Americans who use opioids for chronic pain, and the increased use by teenagers and adults of opioid prescription painkillers for nonmedical purposes. In this application, we describe development of a behavioral paradigm that models 'addiction-like' behavior for opioid drugs, we link this behavior with the expression of key molecular components, and we outline a novel strategy to translate this knowledge into potential therapeutic interventions. Specifically, using this behavioral paradigm, we linked 'addiction-like' behavior for heroin in rats following a one month test period to expression of several key regulators of the mu-opioid receptor (MOR), the primary mediator of the analgesic and rewarding properties of opioid drugs. One of these regulatory proteins is Wntless (WLS), a transport protein necessary for Wnt protein secretion. Wnts are ubiquitous glycoproteins with trophic properties for neurons, including dendritic spine maintenance and increased hippocampal neurogenesis, properties that are normally inhibited by opioid agonist drugs such as morphine, heroin, and fentanyl. Binding of morphine to the MOR enhances the interaction between MOR and WLS, resulting in the inhibition of Wnt protein secretion. Changes in WLS expression were also found to occur in the prefrontal cortex of rats demonstrating addiction-like behaviors for heroin. These results lead to the hypothesis that the opioid-induced MOR/WLS interaction is a critical molecular component contributing to the development of opioid addiction. Experiments proposed in this application are designed to challenge the MOR/WLS hypothesis by testing whether blockade of the MOR/WLS interaction in the prefrontal cortex can prevent acquisition of heroin 'addiction-like' behaviors in rats and/or rescue heroin-experienced rats from 'relapse'. Specific Aim 1 will test whether the disruptive effects of morphine on Wnt secretion can be prevented in vitro via administration of MOR/WLS blocking peptides expressed in a lentiviral vector. Specific Aim 2 will use a viral vector to test whether blockade of the MOR/WLS interaction in the prefrontal cortex will disrupt the development of addiction-like behavior for heroin in drug na¿ve rats, while Specific Aim 3 will use a viral vector to test whether blockade of the MOR/WLS interaction in the prefrontal cortex will disrupt drug-induced reinstatement of heroin-seeking behavior in heroin-experienced rats. If successful, results from the experiments proposed in this application will reveal a novel avenue for the pharmacotherapy of opioid addiction in humans.

描述（由申请人提供）：由于大量美国人使用阿片类药物治疗慢性疼痛，以及青少年和成人越来越多地使用阿片类处方止痛药用于非医疗目的，阿片类药物成瘾已成为一个重大的公共卫生问题。在本申请中，我们描述了一种行为范式的开发，该范式模拟阿片类药物的“成瘾样”行为，我们将这种行为与关键分子成分的表达联系起来，并概述了一种新策略，将这些知识转化为潜在的治疗干预措施。具体来说，利用这种行为范式，我们将“类成瘾”联系起来在为期一个月的测试期后，观察大鼠海洛因的行为，以观察 mu-阿片受体 (MOR) 的几个关键调节因子的表达，MOR 是阿片类药物镇痛和奖励特性的主要介质。这些调节蛋白之一是 Wntless (WLS)，它是 Wnt 蛋白分泌所必需的转运蛋白。 Wnt 是普遍存在的糖蛋白，具有神经元营养特性，包括维持树突棘和增加海马神经发生，这些特性通常会被吗啡、海洛因和芬太尼等阿片类激动剂药物抑制。吗啡与 MOR 的结合增强了 MOR 和 WLS 之间的相互作用，从而抑制 Wnt 蛋白的分泌。还发现 WLS 表达的变化发生在表现出海洛因成瘾样行为的大鼠前额皮质中。这些结果得出这样的假设：阿片类药物诱导的 MOR/WLS 相互作用是导致阿片类药物成瘾发展的关键分子成分。本申请中提出的实验旨在通过测试阻断前额皮质中的 MOR/WLS 相互作用是否可以防止大鼠获得海洛因“成瘾样”行为和/或将有海洛因经历的大鼠从海洛因中解救出来，从而挑战 MOR/WLS 假说。 '复发'。具体目标 1 将测试是否可以通过施用慢病毒载体表达的 MOR/WLS 阻断肽在体外预防吗啡对 Wnt 分泌的破坏作用。具体目标 2 将使用病毒载体来测试阻断前额皮质中的 MOR/WLS 相互作用是否会破坏未吸毒大鼠对海洛因成瘾样行为的发展，而具体目标 3 将使用病毒载体来测试阻断前额皮质中的 MOR/WLS 相互作用是否会破坏海洛因成瘾样行为的发展。前额叶皮质中的 MOR/WLS 相互作用将破坏药物诱导的海洛因实验大鼠的海洛因寻求行为恢复。如果成功，本申请中提出的实验结果将揭示人类阿片类药物成瘾药物治疗的新途径。