Central opioid-induced respiratory depression (OIRD) can cause fatal respiratory arrest. Clinically, patients with sleep apnea (SA) have a higher incidence of fatal OIRD and rescue from OIRD frequently requires a higher dose of the opioid antagonist naloxone. Mechanisms conferring increased susceptibility to OIRD in SA patients have yet to be investigated. I recently established a preclinical model of SA-related OIRD hypersensitivity in which adult rodents are exposed for 8 h/day to 10 cycles/h of hypoxia (21% to 8% O2) with hypercapnia (0% to 8% CO2) for 1 week. This chronic intermittent hypoxia with hypercapnia (CIHHC) model significantly enhances inhibition of inspiratory drive caused by graded doses of the most lethal clinically-relevant opioid, fentanyl. Two brain regions implicated in cardiorespiratory dysfunction are the hypothalamic paraventricular nucleus (PVN) and the nucleus tractus solitarius (NTS). Reciprocal anatomical connections exist between the PVN and NTS and I propose that a homeostatic functional connection also exists. In this model, PVN neurons that project to the respiratory network, including the NTS, are under acute noradrenergic modulation during hypoxia, such as that experienced by the lethal opioid fentanyl. This modulation facilitates PVN-mediated ventilatory chemoreflex responses of the respiratory network, which includes the NTS, thereby conferring protection against OIRD. Hypoxia increases norepinephrine content in the PVN and noradrenergic signaling has been shown to induce endogenous opioid release. Indeed, pilot studies show CIHHC rats have an endogenous opioid tonus in the PVN that tonically suppresses their respiratory drive. Here, I hypothesize that endogenous opioids in the SA/CIHHC PVN oppose enhanced chemoreflex signaling in PVN respiratory neurons that is normally facilitated by chemoreceptor-driven NTS norepinephrine signaling. This effectively prevents noradrenergic protection against OIRD, causing increased sensitivity to OIRD in CIHHC/SA. Proposed experiments will further our understanding of mechanisms underlying respiratory network homeostasis and its disruption by SA, thereby leading to OIRD hypersensitivity.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|