Understanding the Role of Central Parasympathetic Activation in Opioid-Induced Respiratory Depression and Peripheral Airway Constriction

Opioid-induced respiratory depression (OIRD) is a primary cause of mortality resulting from opioid overdose. Numerous mechanisms have been identified as contributors to OIRD, such as the suppression of central respiratory rhythmogenesis. Our recent research revealed that opioids' ability to suppress breathing extends beyond the central suppression of rhythmic activity, notably leading to airway constriction, which can culminate in complete obstruction. The autonomic nervous system plays a pivotal role in regulating the tone of airway smooth muscles with the parasympathetic system being mainly responsible for bronchoconstriction, and the sympathetic system facilitating bronchodilation. In this study, we evaluated the hypothesis that exposure to fentanyl results in the disinhibition of parasympathetic motor output, leading to centrally mediated peripheral airway constriction. After administering fentanyl (500μg/kg i.p.), minute ventilation dropped by nearly 50%, primarily due to a decrease in breathing frequency. Transient airflow obstructions during the inspiratory phase were observed following fentanyl administration, as indicated by an increased latency between diaphragm contraction and the start of inspiratory flow. These airflow obstructions were fully reversed by the sympathomimetics salbutamol or epinephrine. To determine whether the transient obstructions were a result of vagal activation, another group of mice underwent vagotomy prior to fentanyl administration. The vagotomy effectively eliminated the occurrence of airflow obstructions following fentanyl administration. Additionally, using neuronal activity-based fos-dependent labeling and in-vitro patch-clamp recordings, we showed that fentanyl administration led to a pronounced activation of parasympathetic motor neurons within brainstem areas, including the dorsal motor nucleus of the vagus and the nucleus ambiguus. Collectively, our findings suggest that fentanyl induces transient obstructions to airflow that may be attributed to heightened central parasympathetic activity, which in turn drives peripheral airway constriction. P01 HL090554 (J.M.R.), R01 HL126523 (J.M.R.), R01 HL144801 (J.M.R.), R01 HL151389 (J.M.R.), F32 HL154558 (N.J.B.), R00HL145004 (N.A.B.) and R01HL166317 (N.A.B.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.