Heroin Addiction: Predicting Vulnerability & Identification of a Novel Treatment

描述(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，以及青少年和成年人将阿片类药物处方止痛药用于非医疗目的的增加，阿片类药物成瘾已成为一个重大的公共卫生问题。在这一应用中，我们描述了一种行为范式的发展，该范式模拟阿片类药物的“成瘾”行为，我们将这种行为与关键分子成分的表达联系起来，并概述了一种新的策略，将这种知识转化为潜在的治疗干预措施。具体地说，使用这种行为范式，我们将“类似成瘾”联系起来 在一个月的试验期后，大鼠的海洛因行为对阿片类药物止痛和回报特性的主要介体--阿片受体的几个关键调节因子的表达产生影响。其中一个调节蛋白是Wnless(WLS)，这是一种分泌Wnt蛋白所必需的运输蛋白。WNTs是一种普遍存在的糖蛋白，具有神经元的营养特性，包括树突棘维持和增加海马神经发生，这些特性通常被阿片类激动剂药物如吗啡、海洛因和芬太尼抑制。吗啡与MOR的结合增强了MOR和WLS之间的相互作用，从而抑制了Wnt蛋白的分泌。WLS表达的变化也被发现发生在表现出海洛因成瘾行为的大鼠的前额叶皮质。这些结果导致了一种假设，即阿片类药物诱导的MOR/WLS相互作用是导致阿片成瘾形成的关键分子成分。本申请中提出的实验旨在通过测试阻断前额叶皮质的MOR/WLS相互作用是否可以防止大鼠获得类似海洛因的行为和/或拯救经历过海洛因的大鼠免于复发，来挑战MOR/WLS假说。特定目的1将在体外测试吗啡对Wnt分泌的干扰效应是否可以通过给药慢病毒载体中表达的MOR/WLS阻断肽来防止。特定目标2将使用病毒载体来测试阻断前额叶皮质的MOR/WLS相互作用是否会破坏毒品幼稚大鼠海洛因成瘾行为的发展，而特定目标3将使用病毒载体来测试是否阻断 前额叶皮质的MOR/WLS相互作用将干扰海洛因依赖大鼠药物诱导的海洛因寻找行为的恢复。如果成功，本申请中提出的实验结果将揭示人类阿片成瘾药物治疗的新途径。

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.