Differential impact of two critical respiratory centers in opioid-induced respiratory depression in awake mice.

TitleDifferential impact of two critical respiratory centers in opioid-induced respiratory depression in awake mice.
Publication TypeJournal Article
Year of Publication2019
AuthorsVarga AG, Reid BT, Kieffer BL, Levitt ES
JournalJ Physiol
Date Published2019 Oct 07
ISSN1469-7793
Abstract

KEY POINTS: •The main cause of death from opioid overdose is respiratory depression due to the activation of mu opioid receptors (MORs). •We conditionally deleted MORs from neurons in two key areas of the brainstem respiratory circuitry (the Kölliker-Fuse nucleus (KF) or pre-Bötzinger complex (preBötC)) to determine their role in opioid-induced respiratory disturbances in adult, awake mice. •Deletion of MORs from KF neurons attenuated respiratory rate depression at all doses of morphine. •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 apneas. •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 apnea, which correlate with increasing irregularities in breathing pattern. Mu 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 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 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 pattern emerged with many apneas. We conclude that opioids affect distributed areas of the respiratory network and opioid-induced respiratory depression cannot be attributed to only one area in isolation. However, countering the effects of near maximal respiratory depressant doses of opioids in the KF may be a powerful approach to combat opioid overdose. This article is protected by copyright. All rights reserved.

DOI10.1113/JP278612
Alternate JournalJ. Physiol. (Lond.)
PubMed ID31589332