Hind-paw heat stimulation under anesthesia induced a moderate increase in norepinephrine release in the preBötzinger complex, accompanied by correlative changes in respiratory patterns in mice.
Nociceptive stimuli engage neuromodulatory pathways that influence breathing, highlighting a potential mechanism by which pain and stress states modulate respiratory rhythm.
Opioid-induced respiratory depression (OIRD) is the leading cause of death in opioid use, and its severity is tightly linked to arousal state. Norepinephrine (NE) is a critical neuromodulatory neurotransmitter involved in sympathetic nervous system regulation and is a key mediator of the “fight-or-flight” response, influencing multiple physiological systems, including heart rate, blood pressure, and importantly arousal state and respiration. Despite its widespread effects and known link to arousal and respiratory control, the real-time dynamics of norepinephrine release within respiratory circuits remain poorly understood. Here, we employ the genetically encoded G protein–coupled receptor activation–based norepinephrine sensor (GRABNE) to monitor norepinephrine activity in the preBötzinger complex during the Hargreaves thermal nociception test and respiratory challenges. Experiments were conducted in both awake and isoflurane-anesthetized mice to compare state-dependent neuromodulatory responses. We observed a moderate increase in norepinephrine release in the preBötzinger complex in response to hind-paw heat stimulation under anesthesia, accompanied by correlative changes in respiratory patterns. The NE signal displayed a prolonged decay lasting several minutes and a long refractory period, potentially reflecting rapid depletion of releasable NE. These findings suggest that nociceptive stimuli can engage neuromodulatory pathways that influence breathing, highlighting a potential mechanism by which pain and stress states modulate respiratory rhythm. Ongoing experiments aim to further delineate state dependencies and the neural circuits involved, particularly in the context of fentanyl and other opioids, with the goal of clarifying mechanisms underlying OIRD. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Brezinski et al. (Fri,) conducted a other in Opioid-induced respiratory depression. Hargreaves thermal nociception test vs. Awake vs isoflurane-anesthetized states was evaluated on Norepinephrine activity in the preBötzinger complex. Hind-paw heat stimulation under anesthesia induced a moderate increase in norepinephrine release in the preBötzinger complex, accompanied by correlative changes in respiratory patterns in mice.
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