Heroin withdrawal: modulation of aversive states by kappa opioid receptors

描述（由申请人提供）：海洛因成瘾是一种慢性复发性疾病，与重大的社会经济和公共卫生后果有关。海洛因成瘾者在停止使用毒品时会出现严重的烦躁不安和令人厌恶的戒断症状。这些消极的反应是促使许多人复发的关键因素，即使是在长期禁欲之后。人们对戒断后这些反应的神经生物学基础知之甚少，也不知道这种神经生物学如何影响个体复发的可能性。现有证据表明，κ-阿片受体系统在厌恶、烦躁和抑郁状态中起着关键作用。拟议的实验旨在研究κ阿片受体驱动海洛因戒断期间出现的负面情感和奖励相关状态的程度，尽管禁欲，并激发复发。这些实验还将确定κ-阿片受体是否有助于个体复发的脆弱性。本提案的以下目标将使用海洛因成瘾的临床相关模型，其中大鼠长期暴露于递增剂量的海洛因，以解决这些问题。目的1将测量戒断后期间κ-阿片受体的分布和信号传导功能。这些发现将提供有关海洛因戒断相关的持续神经生物学变化的性质的重要细节。目的2将确定这些κ-阿片受体变化的程度是否对应于个体大鼠在戒断后阶段表达的海洛因偏好和/或戒断相关症状的程度。这些发现将确定潜在的行为和/或神经生物学风险因素，有助于个人的复发的可能性。目标3将确定这些行为反应在多大程度上是由大脑的关键动机和情感通路中的κ-阿片受体介导的。一种使用小干扰RNA的创新技术将用于减少腹侧被盖区神经元上κ阿片受体的表达。由于siRNA具有显著的治疗潜力，这些发现将为药物成瘾长期治疗和预防复发的临床干预措施的开发提供信息。总之，这些拟议的研究将扩展我们对κ-阿片受体在海洛因依赖者中如何发挥作用的理解，以及这些受体如何导致戒断后的焦虑和厌恶状态。这项研究还将深入了解个人对成瘾药物的脆弱性的潜在kappa介导机制，这是开发长期预防复发的个性化方法的重要一步。最终，这项研究将拓宽我们对内源性阿片受体系统如何作为成瘾治疗方法进行调节的理解。 公共卫生相关性：海洛因成瘾是一种极其危险和棘手的疾病，与严重的公共卫生和社会经济后果有关，但支持海洛因戒断和戒断的复发倾向状态的神经生物学尚未得到很好的理解。该提案旨在确定主要的神经生物学候选者-κ阿片受体系统-如何有助于为复发奠定基础的戒断相关焦虑和厌恶，以便为长期预防复发的个性化治疗的发展提供信息。

DESCRIPTION (provided by applicant): Heroin addiction is a chronic relapsing disorder associated with significant socioeconomic and public health consequences. Heroin addicts experience severe dysphoria and aversive withdrawal symptoms when drug use is discontinued. These negative responses are crucial factors that motivate relapse in many individuals, even after extended periods of abstinence. Little is known about the neurobiological basis of these responses across the post-withdrawal period, or how this neurobiology contributes to an individual's likelihood of relapse. Existing evidence suggests that the kappa-opioid receptor system plays a key role in states of aversion, dysphoria and depression. The proposed experiments aim to examine the extent to which kappa-opioid receptors drive the negative affective and reward-related states that emerge during heroin withdrawal, persist despite abstinence, and motivate relapse. These experiments will also identify whether kappa-opioid receptors contribute to an individual's vulnerability to relapse. The following Aims of this proposal will use a clinically relevant model of heroin addiction, in which rats are chronically exposed to escalating doses of heroin, to address these questions. Aim 1 will measure the distribution and signaling function of kappa-opioid receptors across the post- withdrawal period. These findings will provide important details about the nature of the persistent neurobiological changes associated with heroin withdrawal. Aim 2 will identify if the degree of these kappa- opioid receptor changes corresponds to the magnitude of heroin preference and/or withdrawal-related symptoms expressed by individual rats across the post-withdrawal period. These findings will identify potential behavioral and/or neurobiological risk factors contributing to an individual's likelihood of relapse. Aim 3 will determine the extent to which these behavioral responses are mediated by kappa-opioid receptors within critical motivation and affective pathways of the brain. An innovative technique using small interfering RNAs will be used to reduce the expression of kappa-opioid receptors on neurons in the ventral tegmental area. As siRNAs have significant therapeutic potential, these findings will inform the development of clinical interventions for the long-term treatment of drug addiction and prevention of relapse. Together, these proposed studies will extend our understanding of how kappa-opioid receptors function in heroin-dependent individuals, and how these receptors contribute to the dysphoria and aversive states that characterize the post-withdrawal period. This research will also provide insight into potential kappa-mediated mechanisms of individual vulnerability to addictive drugs, which represents an important step in the development of personalized approaches to the long-term prevention of relapse. Ultimately, this research will broaden our understanding of how endogenous opioid-receptor systems may be modulated as an approach to addiction therapy. PUBLIC HEALTH RELEVANCE: Nearly one-third of people who take heroin become addicted to it. Heroin addiction is an extremely dangerous and intractable disorder associated with serious public health and socioeconomic consequences, yet the neurobiology supporting the relapse-prone state of heroin withdrawal and abstinence is not well understood. This proposal aims to identify how a prime neurobiological candidate - the kappa-opioid receptor system - contributes to the withdrawal-related dysphoria and aversion that set the stage for relapse, in order to inform the development of personalized therapies for the long-term prevention of relapse.