Chicago, IL 60637
United States
Ph.D. Thesis Defense
Friday, October 18th, 1:00 pm
Caroline Szujewski, CON
Garcia Lab
BSLC Auditorium 205
“Mechanisms mitigating Opioid-Induced Respiratory Depression after repeat fentanyl use”
Abstract: Opioid-induced respiratory depression (ORID) is the hallmark of opioid overdose and a major risk factor for death due to fentanyl. While repeat opioid use (ROU) elevates the risk of death, understanding its influence over breathing and its control has been poorly resolved. Furthermore, while ROU leads to tolerance to opioid overdose susceptibility, this tolerance to the drug effects is conditional and altered by the environmental context of drug administration. We examined how five days of ROU (daily fentanyl injections) impacted the susceptibility of breathing and activity in the preBötzinger complex (preBötC), a brainstem network critical to inspiratory rhythmogenesis, to opioid inhibition. Furthermore, we assessed how susceptibility to OIRD after ROU was altered depending on the context of drug administration and the neural correlates behind this context-dependent tolerance. Acute fentanyl use caused a profound metabolic crisis during ORID involving a mismatch between ventilation and oxygen consumption and aggregate increases in LC activity. Following ROU, rhythmogenesis in the preBötzinger complex was less sensitive to μ-opioid receptor agonism, indicating that adaptation to ROU involves centrally-mediated changes in the inspiratory medullary network. The development of tolerance to OIRD coincided with enhanced LC activity coupled with transient increases in breathing. Changing the context of fentanyl use to a context not previously associated with the drug altered LC activity and its correlation with transient increases in breathing and reduced tolerance to OIRD developed with ROU. Optogenetic activation of the LC minimized OIRD magnitude in fentanyl-naïve subjects. These findings reveal a series of physiological and central adaptations following ROU resulting in improved ventilation and oxygenation during ORID and underscore the importance of the LC in facilitating OIRD tolerance from learned associations during ROU. Failure to establish such associations and the corresponding LC activity may increase susceptibility to overdose and death among chronic opioid users.