Morphine-responsive neurons of the medial habenula : a role in aversive states of morphine withdrawal ?

摘要 阿片类药物靶向于单位阿片受体(MOR)。阿片类药物的使用本质上是由止痛和/或 然而，阿片类药物滥用受到包括厌恶情绪在内的其他因素的强烈推动 阿片类药物戒断方面，这是这项提议的核心。在这里，我们假设莫尔- 内侧缰核表达神经元(以下简称MHB-MOR神经元)在 以阿片类药物戒断为特征的负面情绪反应的发展。该提案是 基于四个前提：(I)MHB已成为成瘾研究中公认的厌恶中心，(Ii) MHB中表达MOR的神经元非常丰富，(3)MHB中表达MOR的神经元 调制厌恶状态(我们最近发表的文章)和(Iv)MOR-MHB神经元投射到中缝核 (RN)，一个主要的情绪控制中心(我们未公布的数据)。 总体而言，我们推测，刺激MHB-MOR神经元增强了负面情绪 阿片类药物戒断的经历，而沉默这些神经元减轻了 戒烟。随着我们创造了一种新的转基因技术，操纵MOR神经元现在已经成为可能 MOR-CRE小鼠品系(未出版)。这些小鼠将被用来操纵两个MHB-MOR神经元 本实验室建立了短期戒断和长时戒断的行为模型。 负面情绪的行为特征及其相关的大脑连接模式将是 学习。目标1将使用光遗传学来询问MHB-MOR神经元在条件反射中的作用 小剂量纳洛酮的位置厌恶和功能磁共振成像表征全脑功能连接(WBFC) 纳洛酮引起的厌恶状态。目标2将使用化学遗传学来询问 抑郁样行为中的MHB-MOR神经元和随时间延长而发展的社会互动缺陷 戒断，和功能磁共振以确定MHB-MOR在WBFC模式改变中的因果作用。 这一提议的创新方面是：(I)重点关注MOR表达神经元的功能 第一次；(Ii)MOR神经元调节厌恶脑中心(MHB)活动的概念， 为阿片类药物戒断的厌恶状态提供了一个尚未探索的机制角度；(Iii) 鲜为人知的神经通路(MHB/IPN/DRN微电路)，与这两种成瘾有很强的相关性 和抑郁研究，(Iv)使用动物功能磁共振成像分析大脑对慢性吗啡的广泛适应 以及(V)人类研究在日益努力抗击阿片类药物危机方面的翻译潜力。 我们期待着发现新的神经机制，这些机制有助于 阿片类药物戒断，与阿片类药物使用障碍有关。从长远来看，功能磁共振成像的特征可能是 可翻译成人类研究。这一建议具有很强的基础和临床意义，并可以独特地 由我们蒙大略省麦吉尔大学道格拉斯研究中心的团队开发。 1

Abstract Opioids target the mu opioid receptor (MOR). Opioid use is essentially motivated by pain relief and/or reward-seeking, however opioid abuse is strongly driven by other factors that include aversive emotional aspects of opioid withdrawal, which are at the center of this proposal. Here, we hypothesize that MOR- expressing neurons of the medial habenula (hereafter called MHb-MOR neurons) play a key role in the development of negative emotional responses characterizing opioid withdrawal. The proposal is based on four premises: (i) the MHb has become a recognized aversion center in addiction research, (ii) MOR-expressing neurons are highly abundant in the MHb, (iii) MOR-expressing neurons of the MHb modulate aversive states (our recent publication) and (iv) MOR-MHb neurons project to the raphe nucleus (RN), a major center for mood control (our unpublished data). Overall, we speculate that stimulating MHb-MOR neurons enhances the negative emotional experience of opioid withdrawal, whereas silencing these neurons alleviates the negative affect of withdrawal. Manipulating MOR-neurons has now become possible, as we have created a new transgenic MOR-Cre mouse line (unpublished). These mice will be used to manipulate MHb-MOR neurons in two behavioral models of short- (Aim 1) and long- (Aim 2) term withdrawal well established in our laboratory, and behavioral hallmarks of negative affect and their associated brain connectivity patterns will be studied. Aim 1 will use optogenetics to interrogate the contribution of MHb-MOR neurons in conditioned place aversion to low dose naloxone, and fMRI to characterize whole brain functional connectivity (WBFC) of the naloxone-evoked aversive state. Aim 2 will use chemogenetics to interrogate the contribution of MHb-MOR neurons in depressive-like behavior and social interaction deficits that develop upon prolonged withdrawal, and fMRI to identify the causal role of MHb-MOR in WBFC patterns alterations. Innovative aspects of this proposal are: (i) the focus on the function of MOR-expressing neurons for the first time; (ii) the notion that MOR neurons modulates activity of an aversion brain center (the MHb), providing a yet unexplored mechanistic angle on aversive states of opioid withdrawal; (iii) the study of a poorly known neural pathway (MHb/IPN/DRN microcircuitry), which has strong relevance to both addiction and depression research, (iv) the analysis of brain wide adaptations to chronic morphine using animal fMRI and (v) the translational potential for human research in growing efforts to fight the opioid crisis. We anticipate discovering novel neural mechanisms contributing to the negative affect of opioid withdrawal, and relevant to opioid use disorders. In the long-term, fMRI signatures may be translatable to human research. This proposal has strong basic and clinical implications, and can uniquely be developed by our team at the Douglas Research Center, McGill University Montréal. 1