Differential impact of two critical respiratory centres in opioid‐induced respiratory depression in awake mice

Abstract

Key pointsr The main cause of death from opioid overdose is respiratory depression due to the activation of µ-opioid receptors (MORs).r We conditionally deleted MORs from neurons in two key areas of the brainstem respiratory circuitry (the Kölliker-Fuse nucleus (KF) and pre-Bötzinger complex (preBötC)) to determine their role in opioid-induced respiratory disturbances in adult, awake mice.r Deletion of MORs from KF neurons attenuated respiratory rate depression at all doses of morphine.r Deletion of MORs from preBötC neurons attenuated rate depression at the low dose, but had no effect on rate following high doses of morphine. Instead, high doses of morphine increased the occurrence of apnoeas.r The results indicate that opioids affect distributed key areas of the respiratory network in a dose-dependent manner and countering the respiratory effects of high dose opioids via the KF may be an effective approach to combat overdose.Abstract The primary cause of death from opioid overdose is respiratory failure. High doses of opioids cause severe rate depression and increased risk of fatal apnoea, which correlate with increasing irregularities in breathing pattern. µ-Opioid receptors (MORs) are widely distributed throughout the brainstem respiratory network, but the mechanisms underlying respiratory depression are poorly understood. The medullary pre-Bötzinger complex (preBötC) and the pontine Kölliker-Fuse nucleus (KF) are considered critical for inducing opioid-related respiratory disturbances. We used a conditional knockout approach to investigate the roles and relative contribution of MORs in KF and preBötC neurons in opioid-induced respiratory depression in Adrienn Varga received her Ph.D. from Case Western Reserve University, where she studied the neural processes underlying navigation in an insect model. This work provided her with an appreciation for how the central nervous system integrates sensory information to shape motor commands. For her postdoctoral work at the University of Florida, she has continued to build on this previous training by moving into the rodent respiratory system, which provides a powerful model for relating sensory cues to the coordination of rhythmic behaviours. An important component of this research is seeking to define the neural mechanisms underlying opioid-induced respiratory depression.A. G. Varga and others J Physiol 598.1 awake adult mice. The results revealed dose-dependent and region-specific opioid effects on the control of both respiratory rate and pattern. Respiratory depression induced by an anti-nociceptive dose of morphine was significantly attenuated following deletion of MORs from either the KF or the preBötC, suggesting cumulative network effects on respiratory rate control at low opioid doses. Deletion of MORs from KF neurons also relieved rate depression at near-maximal respiratory depressant doses of morphine. Meanwhile, deletion of MORs from the preBötC had no effect on rate following administration of high doses of morphine. Instead, a severe ataxic breathing pa...

Opioids depress breathing through two small brainstem sites

“…While this manuscript was in preparation a paper appeared that presents some findings similar to ours ( 26 ).…”

Novel Opioids: Systematic Web Crawling Within the e-Psychonauts’ Scenario

“…Owing to a range of reasons, the non-medical use of opioids such as fentanyl analogs and a range of remaining prescription/nonprescription substances is spreading worldwide (Prekupec et al, 2017;Lovrecic et al, 2019) and is affecting the entire life span, from youngsters to the elderly (Huhn et al, 2018;Kelley-Quon et al, 2019). Opioids are among the most powerful analgesic drugs, but they are burdened by unwanted adverse effects, in particular the abuse liability and the respiratory depression, with the last being the primary cause of death from overdose (Valentino and Volkow, 2018;Algera et al, 2019;Varga et al, 2020). Further, the evidence suggests that opioids' consumption impacts the in utero neuronal development and induces in humans long-lasting transgenerational changes in subsequent generations owing to epigenetic alterations (Gilardi et al, 2018).…”

ß2-Arrestin germline knockout does not attenuate opioid respiratory depression

“…Germline deletion of the µ-opioid receptor gene (Oprm1) completely eliminates OIRD in murine models 5 and selective deletion of Oprm1 within the brainstem medullary breathing rhythm generator, the preBötzinger Complex (preBötC) 6 , greatly attenuates OIRD in normoxic and hypercapnic air 7,8 . When engaged, MOR Gi-protein signaling activates inwardly rectifying potassium channels 9 and inhibits synaptic vesicle release 10 , thereby depressing neural signaling.…”