Grant: Fellowship - PA - Sleep and Circadian Rhythms (Biomedical)

Opioids are used extensively for their analgesic properties but they have a variety of unwanted side effects, including tolerance, dependence, and most signicantly, respiratory depression. According to the Public Health Agency of Canada, there were more than 8,000 apparent opioid-related deaths in Canada between January 2016 and March 2018, an epidemic responsible for thousands of emergency visits every year, therefore causing a severe social, health and financial burden. The analgesic effects of opioids result from activation of classical opioid receptors (MORs) in the central nervous system and no treatments are currently available to prevent respiratory depression without reducing their analgesic proprieties. MORs are expressed in various brain structures regulating breathing including the preBötzinger Complex (preBötC). The preBötC is composed of neuronal subpopulations expressing neurokinin-1 receptors (NK1-R) and the peptide somatostatin (SST). We propose that genetic deletion of MORs in NK1-R and SST cells, pharmacological activation of NK1-R and antagonism of SST as well as optogenetic stimulation of said cells will reduce opioids-induced respiratory depression. My project aims to determine whether NK1-R and SST cells are sensitive to MOR ligands and whether they regulate opioid-induced respiratory depression and sedation To do so, we will use a variety of physiological (electrocortical and respiratory recordings), pharmacological (MORs agonist injection) and genetic (MORs deletion) approaches. My research hypothesis will open a new path towards the understanding of respiratory depression with opioids abuse, an essential step to develop new therapeutic targets to reduce the risk of opioids overdose, hypoxemia, critical care, and mortality. The benefits will be significant both from a fundamental and clinical point of view.