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...

The Kölliker‐Fuse nucleus (KF) is a functionally distinct component of the parabrachial complex, located in the dorsolateral pons of mammals. The KF has a major role in respiration and upper airway control. A comprehensive understanding of the KF and its contributions to respiratory function and dysfunction requires an appreciation for its neurochemical characteristics. The goal of this review is to summarize the diverse neurochemical composition of the KF, focusing on the neurotransmitters, neuromodulators, and neuropeptides present. We also include a description of the receptors expressed on KF neurons and transporters involved in each system, as well as their putative roles in respiratory physiology. Finally, we provide a short section reviewing the literature regarding neurochemical changes in the KF in the context of respiratory dysfunction observed in SIDS and Rett syndrome. By over‐viewing the current literature on the neurochemical composition of the KF, this review will serve to aid a wide range of topics in the future research into the neural control of respiration in health and disease.

Impaired chemoreflex responses are a central feature of opioid-induced respiratory depression, however, the mechanism through which mu opioid receptor agonists lead to diminished chemoreflexes is not fully understood. One brainstem structure involved in opioid-induced impairment of chemoreflexes is the nucleus of the solitary tract (NTS), which contains a population of neurons that express mu opioid receptors. Here, we tested whether caudal NTS neurons activated during the chemoreflex challenge express mu opioid receptors and overlap with neurons activated by opioids. Using genetic labeling of mu opioid receptor-expressing neurons and cFos immunohistochemistry as a proxy for neuronal activation, we examined the distribution of activated NTS neurons following hypercapnia, hypoxia, and morphine administration. The main finding was that hypoxia and hypercapnia primarily activated NTS neurons that did not express mu opioid receptors. Furthermore, concurrent administration of morphine with hypercapnia induced cFos expression in non-overlapping populations of neurons. Together these results suggest an indirect effect of opioids within the NTS, which could be mediated through mu opioid receptors on afferents and/or inhibitory interneurons.

Respiratory depression is the main cause of death from an opioid overdose. The reduction in respiratory rate is the result of activation of mu opioid receptors in respiratory centers, such as the pontine Kölliker‐Fuse nucleus and the medullary pre‐Bötzinger complex. The goal of this study was to directly compare the relative contribution of opioid‐sensitive neurons in the Kölliker‐Fuse nucleus and the pre‐Bötzinger complex to respiratory depression caused by systemic administration of the opioid agonist morphine in adult mice. We conditionally knocked out mu opioid receptors using virally mediated Cre expression in mice with floxed mu opioid receptors. Whole‐cell patch clamp recordings in acute brain slices showed that this approach successfully eliminates mu opioid receptor‐mediated outward currents from Kölliker‐Fuse nucleus neurons. Next, using plethysmography, we found that deletion of mu opioid receptors from either the Kölliker‐Fuse nucleus or pre‐Bötzinger complex attenuated the decrease in respiratory rate induced by an analgesic dose of morphine (10mg/kg). Administration of high doses of morphine (30mg/kg and 100mg/kg) resulted in reduced respiratory rates similar to that observed in control animals. Morphine administration also caused an increased level of irregularity in the breathing pattern with short intervals of fast and slow breathing and an increased number of apneas. These effects were dependent on the administered dose of morphine, as well as the location of mu opioid receptor removal. Our results indicate that multiple pontine and medullary respiratory groups differentially contribute to morphine‐induced respiratory depression, and none are entirely responsible for the effects of morphine.Support or Funding InformationThis work was supported by National Institutes of Health Grants DA038069 (E.S.L.) and DA05010 (B.L.K.). A.G.V. was funded by the UF Breathing Research and Therapeutics Training Program (T32 HL134621) and the Center for Respiratory Research and Rehabilitation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

INTRODUCTION:The dynamic interplay between several large-scale brain networks is thought to underlie human consciousness. The default mode network (DMN) governs internal thought during rest, the central executive network (CEN) drives goal-directed problem solving, and the salience network (SN) detects and integrates new stimuli during the transition between resting and cognitively active states. While scalp electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) have elucidated much about these networks in steady states, intracranial EEG (iEEG) dynamics during state transitions remain largely unclear.METHODS:Seven patients with medically refractory epilepsy underwent robot-assisted stereotactic placement of depth electrodes for epileptic focus localization. Recordings from 422 total iEEG contacts representing 49 distinct cognitive network nodes were obtained during anesthesia emergence. Local-field dynamics and Observer’s Assessment of Alertness/Sedation (OAAS) scale state were analyzed in 20s clips for complexity, functional connectivity (FC), and graph communicability metrics.RESULTS:Signal complexity as represented by mean multiscale sample entropy (MSE) of SN and DMN nodes increases significantly during emergence from anesthesia (P < 0.05), driven by a shift from low- to mid-frequency power in key nodes. Intermediate consciousness states demonstrated higher mean MSE and participation coefficient, representing early integrative network behavior, before reaching an optimal balance of segregation and integration at wakefulness. During emergence, between-network FC increased most strongly between SN and CEN nodes. Communicability of SN nodes increased during emergence, driven predominately by increasing communicability of right anterior insula.CONCLUSIONS:Intracranial electroencephalographic recording of brain activity during anesthesia emergence demonstrates a complex but quantifiable interplay of default mode, central executive, and salience network hubs. There may be a greater than previously understood role of right anterior insula in gating transitions in consciousness states.