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，因为它在调节基本生理功能如疼痛和奖赏/成瘾方面具有重要意义。除了疼痛通路和奖赏中心，阿片受体和肽也存在于中枢神经系统的各个区域，其中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/嗅束中的作用尚未得到解决。此外，阿片受体在特定神经元群体以及小胶质细胞中的存在似乎是有争议的。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。** 拟议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涉及的信号级联。** 短期目标的简要概述：* 短期目标1：研究MOP和DOP在主要嗅球中的作用 * 使用我实验室中的独特工具以及市售小鼠模型，我们将研究定位并鉴定MOP和DOP表达细胞在嗅球/嗅束内的投射。我们还将使用药理学和行为方法研究它们在该结构中的作用。*短期目标2：研究小胶质细胞中的DOP * 使用我们的基因工程小鼠以及市售模型，我们将产生DOP将在小胶质细胞中选择性表达（条件敲入）的小鼠品系。然后将进行药理学和行为学测试，以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MOP和DOP参与的新型信号级联 * 我们将使用邻近标记方法（APEX 2融合到MOP和DOP的C-末端尾部）鉴定和研究这些受体的新型信号伴侣以解开它们的“信号体”。结合质谱分析，该测定将用于鉴定这些受体的新型信号传导伴侣。拟议的研究将提供对阿片系统和不同信号级联的更深入理解，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。拟议的研究计划还提供了一个机会，在舍布鲁克药理学研究所提供的巨大环境中培训HQP阿片系统。

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.