Mechanisms of repeated opioid use dependent remodeling in respiratory control

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PROJECT SUMMARY Overdose deaths related to synthetic opioids have increased six-fold over the past 20 years. Repeated opioid users, such as individuals suffering from substance use disorder, are at the greatest risk for opioid induced respiratory depression, the hallmark of overdose. Although extensive understanding into the cellular, circuit and pharmacological basis by which opioids suppress breathing exists, how repeated opioid use impacts the control of breathing has been largely understudied. This is despite the clinical and laboratory evidence indicating that repeated opioid use significantly changes the control of breathing. This knowledge gap contributes to the limited ability to address opioid overdose among repeat opioid users—the population most vulnerable to overdose death. Even among repeat opioid users, tolerance to opioid induced respiratory depression can be labile. It is well-recognized that tolerance to the analgesic and euphoric effects of opioids has context-dependence. Similarly, the susceptibility to opioid overdose can be influenced by the context in which these drugs are used. Yet, the contribution of context-dependent mechanisms to the susceptibility of opioid induced respiratory depression is unknown. We developed a model of repeated fentanyl use that produces changes in breathing consistent with the breathing phenotype observed in repeated opioid users—including a form of tolerance dependent on context. The primary objective of this proposal is to examine the mechanisms involved with repeated opioid use-dependent remodeling in the control of breathing. We hypothesize that repeated opioid use remodels the control of breathing through direct cellular changes in the respiratory network and through the emergence of a labile form of tolerance dependent on behavioral conditioning and neuromodulation within the respiratory network. This work will examine: (1) the cellular and the neurophysiological mechanisms that underlie the remodeling of the control of breathing after repeated opioid use; (2) the contribution that learned behavior has in producing state-dependent breathing and influencing opioid susceptibility; and (3) the role that neuromodulation plays in influencing the stability of inspiratory drive prior to and after repeated opioid use. Thus, this work provides a much-needed mechanistic framework for understanding how repeated opioid use remodels the control of breathing. Such a framework can serve as a foundation for novel approaches and therapies to address the risk of opioid overdose in individuals most vulnerable to overdose-death and respiratory-associated co-morbidities.