Neural and physiological state dependency of opioid induced respiratory depression

Abstract

Opioid induced respiratory depression (OIRD) is the major cause of death associated with opioid overdose. Within the brainstem, respiratory activity is generated within the ventrolateral medulla in an opioid-sensitive region known as the PreBötzinger Complex (PreBötC). Within the PreBötC a heterogenous network of neurons under continuous influence by excitatory and inhibitory neuromodulators culminate to form synchronized bursting that results in inspiratory activity. Additionally, the PreBötC network dynamically interacts with the physiological processes that give rise to ventilation. Understanding the interplay between neural and physiological states of the in-vivo system will be key to overcoming OIRD. Here, we tested whether increasing the excitatory state of the PreBötC in-vivo by non-specific K + channel inhibition, or elevated norepinephrine destabilizes breathing, but creates a network state resistant to OIRD. Further, we tested whether the state of upper airway patency following opioid administration influences sensitivity of the PreBötC to OIRD. Following microdialysis into the PreBötC of the non-specific K + channel antagonist, tetraethylammonium (TEA)(10mM), or 1mM norepinephrine ventilation increased and breathing became erratic with variable frequency and tidal volume. However, following 150mg/kg morphine, breathing re-stabilized and returned to near control levels. These results demonstrate that determining the neuromodulatory state of excitability within the PreBötC prior to opioid administration may help to better predict and prevent OIRD. To determine whether the physiological state of the upper-airway following opioid administration can affect sensitivity of the PreBötC to OIRD we tested the ventilatory response to opioids in both airway-intact and tracheostomized mice in-vivo. For these experiments we utilized fentanyl, due to it’s known effects on disrupting upper airway function. Following administration of 500μg/kg fentanyl airway in-tact mice displayed increased upper airway resistance with regular periods of obstructive apnea, severe hypoxemia and reduced breathing frequency that eventually resulted in complete cessation of respiratory activity. Conversely, mice receiving 500μg/kg fentanyl following tracheostomy showed significantly less respiratory suppression and no apneic periods, compared to airway in-tact mice. However, following administration of a hypoxic gas mixture (10% O2) tracheostomized mice experienced terminal apnea in the presence of 500μg/Kg fentanyl. These results demonstrate that hypoxemia experienced following fentanyl administration, which is exacerbated by upper airway constriction may increase the risk of fatal OIRD in-vivo. Together our data suggest that understanding OIRD within the in-vivo system requires the careful investigation of integrative mechanisms between the neural and physiological processes that give rise to overall ventilation. This work was supported by NIH grants: HL154558 (NJB), HL145004 (NEB), HL126523 (JMR), HL144801 (JMR) This is the full abstract presented at the American Physiology Summit 2023 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.