Heroin Addiction: Predicting Vulnerability & Identification of a Novel Treatment

海洛因成瘾：预测脆弱性

• 批准号: 8722795
• 负责人: ROBERT LEVENSON
• 金额: $ 19.13万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722795
• 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

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 naïve 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（通过应用程序提供）：由于大量使用阿片类药物用于慢性疼痛的美国人，对阿片类药物的成瘾已成为一个实质性的公共卫生问题，而阿片类药物处方止痛药的青少年和成年人用于非医学目的。在此应用中，我们描述了对阿片类药物的“成瘾”行为的行为范式的发展，我们将这种行为与关键分子成分的表达联系起来，并概述了将这种知识转化为潜在治疗干预措施的新型策略。具体来说，使用此行为范式，我们将“成瘾状”链接起来 在一个月的测试期间，在大鼠中，海洛因的行为表达了Mu-Apiole受体（MOR）的几个关键调节剂，这是阿片类药物的镇痛和奖励性能的主要介体。这些调节蛋白之一是Wntless（WLS），这是Wnt蛋白分泌所需的转运蛋白。 WNT是无处不在的糖蛋白，具有神经元的营养特性，包括树突状脊柱维持和增加的海马神经发生，通常被阿片类激动剂药物（例如吗啡，海洛因和芬太尼）抑制的特性。吗啡与MOR的结合增强了MOR与WL之间的相互作用，从而抑制Wnt蛋白分泌。还发现WLS表达的变化发生在大鼠的前额叶皮层中，表明海洛因的成瘾行为。这些结果导致了一个假设，即阿片类药物诱导的MOR/WLS相互作用是有助于阿片类药物成瘾发展的关键分子成分。本应用程序中提出的实验旨在通过测试前额叶皮层中MOR/WLS相互作用的阻滞来挑战MOR/WLS假设，可以防止大鼠中的海洛因“成瘾”行为和/或救援海洛因 - 经验丰富的大鼠从“复发”中获取海洛因“成瘾”行为。特定目标1将测试吗啡对Wnt分泌的破坏性作用是否可以在慢病毒载体中表达的MOR/WLS阻断Petides进行体外预​​防。具体目标2将使用病毒矢量来测试在前额叶皮层中对MOR/WLS相互作用的封锁是否会破坏药物幼稚大鼠中海洛因的成瘾行为的发展，而特定的AIM 3则使用病毒矢量来测试是否封锁对封锁的封锁 前额叶皮层中的MOR/WLS相互作用将破坏药物诱发的海洛因经验老鼠中寻求海洛因的行为。如果成功的话，本应用程序中提出的实验的结果将揭示出人类阿片类成瘾药物疗法的新途径。