Heroin Addiction: Predicting Vulnerability & Identification of a Novel Treatment

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发展，该范式为阿片类药物的“成瘾样”行为建模，我们将这种行为与关键分子组分的表达联系起来，并且我们概述了一种将这种知识转化为潜在治疗干预的新策略。具体地说，使用这种行为范式，我们将“上瘾” 在一个月的测试期后，大鼠中海洛因的行为与μ-阿片受体（莫尔）的几种关键调节剂的表达有关，μ-阿片受体是阿片类药物的镇痛和奖励性质的主要介质。这些调节蛋白之一是Wntless（WLS），Wnt蛋白分泌所必需的转运蛋白。Wnt是一种普遍存在的糖蛋白，具有神经元的营养特性，包括树突棘的维持和海马神经发生的增加，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。吗啡与莫尔的结合增强了莫尔和WLS之间的相互作用，导致Wnt蛋白分泌的抑制。WLS表达的变化也被发现发生在表现出海洛因成瘾样行为的大鼠的前额叶皮层。这些结果导致阿片诱导的莫尔/WLS相互作用是阿片成瘾发展的关键分子组分的假设。本申请中提出的实验设计为通过测试阻断前额叶皮层中的莫尔/WLS相互作用是否可以防止大鼠获得海洛因“成瘾样”行为和/或拯救经历过海洛因的大鼠免于成瘾，来挑战莫尔/WLS假说。 “复发”具体目标1将测试吗啡对Wnt分泌的破坏性作用是否可以通过施用在慢病毒载体中表达的莫尔/WLS阻断肽在体外预防。特异性目标2将使用病毒载体来测试前额叶皮层中的莫尔/WLS相互作用的阻断是否会破坏药物初治大鼠中海洛因成瘾样行为的发展，而特异性目标3将使用病毒载体来测试阻断前额叶皮层中的MOR/WLS相互作用是否会破坏药物初治大鼠中海洛因成瘾样行为的发展。 前额叶皮层中的莫尔/WLS相互作用将破坏经历过海洛因的大鼠中药物诱导的海洛因寻求行为的恢复。如果成功，本申请中提出的实验结果将揭示人类阿片类药物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 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.