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

摘要 阿片类药物靶向μ阿片受体（莫尔）。阿片类药物的使用主要是为了缓解疼痛和/或 然而，阿片类药物滥用受到其他因素的强烈驱动，包括厌恶情绪 阿片类药物戒断的方面，这是这项建议的中心。在这里，我们假设莫尔- 内侧缰核的表达神经元（下文称为MHb-MOR神经元）在神经元的表达中起关键作用。 发展以阿片类药物戒断为特征的负面情绪反应。该提案 基于四个前提：（i）MHb已经成为成瘾研究中公认的厌恶中心，（ii） MHb中表达M0 R的神经元是高度丰富的，（iii）MHb中表达M0 R的神经元 调制厌恶状态（我们最近的出版物）和（iv）MOR-MHb神经元项目中缝核 (RN)，一个主要的情绪控制中心（我们未发表的数据）。 总的来说，我们推测刺激MHb-MOR神经元会增强负面情绪， 阿片类药物戒断的经验，而沉默这些神经元消除了负面影响， 戒断操纵MOR神经元现在已经成为可能，因为我们已经创造了一种新的转基因 MOR-Cre小鼠系（未发表）。这些小鼠将用于在两个实验中操纵MHb-MOR神经元。 短期（目标1）和长期（目标2）戒断行为模型在我们的实验室已经建立， 消极情绪的行为特征和与之相关的大脑连接模式 研究了目的1将使用光遗传学来询问MHb-MOR神经元在条件反射中的贡献。 对低剂量纳洛酮的位置厌恶，以及fMRI表征全脑功能连接（WBFC） 纳洛酮诱发的厌恶状态目标2将使用化学遗传学来询问 MHb-MOR神经元在抑郁样行为和社会互动缺陷中的作用， 撤药，和fMRI，以确定MHb-MOR在WBFC模式改变中的因果作用。 该提议的创新方面是：（i）关注表达MOR的神经元的功能， 第一次;（ii）莫尔神经元调节厌恶脑中心（MHb）活动的概念， 提供了一个尚未探索的机制的角度对阿片类药物戒断的厌恶状态;（iii）的研究， 已知较少的神经通路（MHb/IPN/DRN微电路），与成瘾和 和抑郁症的研究，（iv）使用动物fMRI分析大脑对慢性吗啡的适应性 以及（v）人类研究在日益努力应对阿片类药物危机方面的转化潜力。 我们期待发现新的神经机制，有助于负面影响， 阿片类药物戒断，并与阿片类药物使用障碍有关。从长远来看，功能性磁共振成像信号可能是 可用于人类研究。这项建议具有很强的基础和临床意义， 由蒙特利尔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recent publication) and (iv) MOR-MHb neurons project to the raphe nucleus (RN), a major center for mood control (our unpublished data).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 Manipulating MOR-neurons has now become possible, as we have created a new transgenic MOR-Cre mouse line (unpublished).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