Neurobiology and molecular mechanisms of the opioid system

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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 bulbUsing 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 microgliaUsing 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 DOPWe 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.