Neurobiology and molecular mechanisms of the opioid system

阿片系统是研究最多的神经肽系统之一，因为它在调节疼痛和奖励/成瘾等基本生理功能方面具有重要意义。除了疼痛通路和奖励中枢，阿片受体和肽也存在于中枢神经系统的各个区域，它们的作用和功能尚未被描述和/或仍然知之甚少。例如，阿片系统在嗅球/嗅道中的作用尚未得到解决。此外，阿片受体在特定神经元群和小胶质细胞中的存在存在争议。最后，参与阿片配体及其受体作用的信号级联仍有待充分描述。******提出的研究计划的总体目标是进一步了解阿片系统，特别强调未探索的大脑区域和细胞群，以及阿片受体激活所参与的信号级联反应。******短期目标概述：***短期目标1：研究MOP和DOP在主嗅球中的作用***利用我实验室独有的工具和市售的小鼠模型，我们将研究MOP和DOP表达细胞在嗅球/嗅束内的定位和定位。我们还将使用药理学和行为学方法研究它们在这种结构中的作用。***短期目标2：研究DOP在小胶质细胞中的作用***利用我们的基因工程小鼠以及市售模型，我们将产生DOP在小胶质细胞中选择性表达（条件敲入蛋白）的小鼠品系。药理学和行为学测试将被用来确定阿片系统在这些细胞中的作用和功能。***短期目标3：发现和表征由MOP和DOP参与的新型信号级联***我们将使用接近标记方法（APEX2融合到MOP和DOP的c端尾部）识别和研究这些受体的新型信号伙伴，以解开它们的“信号体”。结合质谱分析，该分析将用于识别这些受体的新信号伙伴。******提出的研究将提供对阿片系统和不同信号级联的更深入的理解，这两个方面对于充分理解阿片系统的一系列功能至关重要。拟议的研究项目还为在舍布鲁克药理学研究所提供的巨大环境中培训HQP提供了阿片类药物系统的机会。

The opioid system is one of the most studied neuropeptide systems because of its significant implication in regulating essential physiological functions such as pain and reward/addiction. Aside pain pathways and reward centers, opioid receptors and peptides are also present in various regions of the central nervous system where their roles and functions have not yet been described and/or remain poorly understood. For instance, the role of the opioid system in the olfactory bulb/tract has not been solved. Additionally, the presence of the opioid receptors in specific neuronal populations as well as in microglia appears controversial. Finally, the signaling cascades involved in the action of the opioid ligands and their receptors remain to be fully described. ******The overarching goal of the proposed research program is to further our knowledge of the opioid system, with a particular emphasis on unexplored brain regions and populations of cells as well as on the signaling cascades engaged by the activation of the opioid receptors. ******Brief outline of the short-term goals:***Short-term goal 1: Investigate the role of MOP and DOP in the main olfactory bulb***Using unique tools in my lab together with commercially available mouse models, we will study the localization and identify the projections of MOP and DOP expressing cells within the olfactory bulb/tract. We will also investigate their roles in this structure using pharmacological and behavioral approaches.***Short-term goal 2: Study DOP in microglia***Using our genetically-engineered mice as well as commercially available models, we will generate mouse lines in which DOP will be selectively expressed (conditional knockins) in microglia. Pharmacological and behavioral tests will then be employed to determine roles and functions of the opioid system in these cells.***Short-term goal 3: Discover and characterize novel signaling cascades engaged by MOP and DOP***We will identify and study novel signaling partners for these receptors using a proximity-labeling approach (APEX2 fused to the C-terminal tail of MOP and DOP) to unravel their “signalosome”. Combined to mass spectrometry, this assay will be used to identify novel signaling partners for these receptors.******The proposed research will provide a greater depth of understanding of the opioid system and the different signaling cascades, two aspects essential for fully understanding the array of functions of the opioid system. The proposed research program also provides an opportunity for training HQP on the opioid system in the tremendous environment offered at the Sherbrooke's Institute of Pharmacology.