Optogenetic stimulation of Phox2b-expressing neurons in the respiratory parafacial region rescue fentanyl-induced respiratory depression

The primary cause of death from opioid overdose is opioid-induced respiratory depression (OIRD), which results in substantial suppression of respiratory rate, destabilization of breathing patterns, severe hypercapnia, and a heightened risk for life-threatening apnea. A crucial chemosensitive brainstem region, located in the rostral ventrolateral medullary reticular formation, contains a bilateral cluster of approximately 800 non-opioid receptor-expressing glutamatergic, non-catecholaminergic, Phox2b+ propriobulbar neurons. These neurons are stimulated by CO2 and acidification and play a vital role in regulating breathing to prevent respiratory acidosis. Under normal circumstances, opioid induced hypercapnia should stimulate these cells to restore ventilation and prevent disturbances in arterial blood gases. However, during OIRD, it remains unclear whether these neurons can effectively rescue breathing in the response to opioid induced hypercapnia. The present study aims to address this question by investigating whether the ability of these neurons to stimulate breathing is significantly altered during opioid-induced respiratory depression. Using optogenetic stimulation, we stimulated these Phox2b+ cells before and after fentanyl to test for whether their ability to stimulate ventilation is reduced during OIRD. As expected, fentanyl (500 μg/kg, ip) resulted in respiratory rate suppression and destabilization of breathing pattern. Before fentanyl administration optogenetic stimulation of Phox2b+ cells increased breathing activity in a pulse stimulation frequency dependent (5-20Hz) manner. Unexpectedly, following fentanyl administration, similar optogenetic stimulation of Phox2b+ cells resulted in a significantly greater frequency dependent (5-20Hz) increase in breathing activity compared to pre-fentanyl levels. Additionally, both hypercapnia (FiCO2 = 0.1) or hypoxia (FiO2 = = 0.1) produced an increase breathing activity in a similar manner in pre- and post-fentanyl conditions. The results suggest that fentanyl paradoxically increases the ability of Phox2b+ cells to stimulate breathing but shifts the steady-state relationship between ventilation and arterial blood gases, such that resting ventilation is reduced. FAPESP, NIH. 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.