scholarly journals Electrocortical changes associating sedation and respiratory depression by the opioid analgesic fentanyl

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Gaspard Montandon ◽  
Richard L. Horner
Keyword(s):  
Respiratory Rate ◽  
Respiratory Depression ◽  
Respiratory Activity ◽  
Opioid Analgesic ◽  
Respiratory Network ◽  
Opioid Drugs ◽  
Freely Behaving ◽  
New Evidence ◽  
Frequency Power ◽  
Brain Arousal

Abstract Opioid drugs are the mainstay of pain management but present the side-effect of respiratory depression that can be lethal with overdose. In addition to their respiratory effect, opioids also induce a profound sedative state and produce electrocortical features characteristic of a state of reduced brain arousal, similar to anaesthesia or sleep. In such states, respiratory activity depends more on the integrity of the brainstem respiratory network than it does during wakefulness. Accordingly, we propose that sedation by fentanyl induces specific electrocortical changes consistent with reduced brain arousal, and that the magnitude of respiratory depression is associated with distinct electrocortical changes. To these aims, we determined the effects of systemic injections of fentanyl (dosage 100 µg ·kg) versus control on electrocortical  and respiratory activities of freely-behaving rats. We found that fentanyl induced electrocortical changes that differed from those observed in sleep or wakefulness. Fentanyl increased δ (1–3 Hz) frequency power (P < 0.001), but reduced α (7.5–13.5 Hz) and β2 (20–30 Hz) powers (P = 0.012 and P < 0.001, respectively), when compared to wakefulness. Interestingly, respiratory rate depression by fentanyl was significantly correlated with increased θ power (R = 0.61, P < 0.001), therefore showing a clear association between electrocortical activity and the magnitude of respiratory rate depression. Overall, we provide new evidence linking specific electrocortical changes to the severity of respiratory depression by opioids, which highlights the importance of considering the cortical and subcortical effects of opioids in addition to their impacts on breathing when evaluating opioid-induced respiratory depression.

Respiratory depression produced by activation of GABA receptors in hindbrain of cat

1981 ◽  
Vol 51 (5) ◽  
pp. 1278-1286 ◽  
Author(s):  
K. A. Yamada ◽  
P. Hamosh ◽  
R. A. Gillis
Keyword(s):  
Tidal Volume ◽  
Respiratory Rate ◽  
Respiratory Depression ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Respiratory Activity ◽  
Aminobutyric Acid ◽  
Neural Pathways ◽  
Gamma Aminobutyric Acid ◽  
Respiratory Responses

Respiratory responses to activation of gamma-aminobutyric acid (GABA) receptors in the hindbrain were measured in chloralose-anesthetized cats using a Fleisch pneumotachograph. GABA receptors were activated by intracisternal injections of muscimol and GABA. Muscimol (0.05--6.65 micrograms) administered to seven animals caused a depression of respiratory activity with apnea occurring in each animal. Before apnea occurred, a decrease in tidal volume was observed (from 25.7 +/- 0.9 to 14.7 +/- 1.1 ml). Respiratory rate and inspiratory and expiratory durations were unchanged. GABA (0.05--12.15 mg) administered to five animals produced the same effect as muscimol on respiratory activity. Apnea produced by both agents was reversed by intracisternal administration of the GABA-receptor antagonist drug, bicuculline. Administration of bicuculline to four naive animals increased tidal volume (from 31.3 +/- 1.7 to 36.5 +/- 0.7 ml) but had no effect on either respiratory rate or inspiratory duration. These results indicate that activation of GABA receptors causes respiratory depression and suggest that GABA may be an important neurotransmitter in CNS neural pathways involved in regulating respiratory activity.

scholarly journals Respiratory depression and analgesia by opioid drugs in freely-behaving larval zebrafish

2020 ◽  
Author(s):  
Shenhab Zaig ◽  
Carolina Scarpellini ◽  
Gaspard Montandon
Keyword(s):  
Respiratory Depression ◽  
Opioid Receptor ◽  
Mu Opioid Receptor ◽  
Receptor System ◽  
Mu Opioid ◽  
Larval Zebrafish ◽  
Opioid Receptor Antagonists ◽  
Opioid Drugs ◽  
Fast Development ◽  
Freely Behaving

AbstractAn opioid epidemic is spreading in North America with millions of opioid overdoses annually. Opioid drugs, like fentanyl, target the mu opioid receptor system and induce potentially lethal respiratory depression. The challenge in opioid research is to find a safe pain therapy with analgesic properties but no respiratory depression. Current discoveries are limited by lack of amenable animal models to screen candidate drugs. Zebrafish (Danio rerio) is an emerging animal model with high reproduction and fast development, which shares remarkable similarity in their physiology and genome to mammals. However, it is unknown whether zebrafish possesses similar opioid system, respiratory and analgesic responses to opioids than mammals. In freely-behaving larval zebrafish, fentanyl depresses the rate of respiratory mandible movements and induces analgesia, effects reversed by mu-opioid receptor antagonists. Zebrafish presents evolutionary conserved mechanisms of action of opioid drugs, also found in mammals, and constitute amenable models for phenotype-based drug discovery.

scholarly journals Respiratory depression and analgesia by opioid drugs in freely-behaving larval zebrafish

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Shenhab Zaig ◽  
Carolina da Silveira Scarpellini ◽  
Gaspard Montandon
Keyword(s):  
Respiratory Depression ◽  
Opioid Receptor ◽  
Mu Opioid Receptor ◽  
Receptor System ◽  
Mu Opioid ◽  
Larval Zebrafish ◽  
Opioid Receptor Antagonists ◽  
Opioid Drugs ◽  
Fast Development ◽  
Freely Behaving

An opioid epidemic is spreading in North America with millions of opioid overdoses annually. Opioid drugs, like fentanyl, target the mu opioid receptor system and induce potentially lethal respiratory depression. The challenge in opioid research is to find a safe pain therapy with analgesic properties but no respiratory depression. Current discoveries are limited by lack of amenable animal models to screen candidate drugs. Zebrafish (Danio rerio) is an emerging animal model with high reproduction and fast development, which shares remarkable similarity in their physiology and genome to mammals. However, it is unknown whether zebrafish possesses similar opioid system, respiratory and analgesic responses to opioids than mammals. In freely-behaving larval zebrafish, fentanyl depresses the rate of respiratory mandible movements and induces analgesia, effects reversed by mu-opioid receptor antagonists. Zebrafish presents evolutionary conserved mechanisms of action of opioid drugs, also found in mammals, and constitute amenable models for phenotype-based drug discovery.

scholarly journals Vagal feedback in the entrainment of respiration to mechanical ventilation in sleeping humans

2000 ◽  
Vol 89 (2) ◽  
pp. 760-769 ◽  
Author(s):  
Peggy M. Simon ◽  
Alfred M. Habel ◽  
J. Andrew Daubenspeck ◽  
J. C. Leiter
Keyword(s):  
Mechanical Ventilation ◽  
Respiratory Rate ◽  
Eye Movement ◽  
Lung Transplant ◽  
Respiratory Activity ◽  
Nrem Sleep ◽  
Normal Subjects ◽  
The Other ◽  
Absolute Requirement ◽  
Striking Contrast

We studied the capacity of four “normal” and six lung transplant subjects to entrain neural respiratory activity to mechanical ventilation. Two transplant subjects were studied during wakefulness and demonstrated entrainment indistinguishable from that of normal awake subjects. We studied four normal subjects and four lung transplant subjects during non-rapid eye movement (NREM) sleep. Normal subjects entrained to mechanical ventilation over a range of ventilator frequencies that were within ±3–5 breaths of the spontaneous respiratory rate of each subject. After lung transplantation, during which the vagi were cut, subjects did demonstrate entrainment during NREM sleep; however, entrainment only occurred at ventilator frequencies at or above each subject's spontaneous respiratory rate, and entrainment was less effective. We conclude that there is no absolute requirement for vagal feedback to induce entrainment in subjects, which is in striking contrast to anesthetized animals in which vagotomy uniformly abolishes entrainment. On the other hand, vagal feedback clearly enhances the fidelity of entrainment and extends the range of mechanical frequencies over which entrainment can occur.

Reconfiguration of the Respiratory Network at the Onset of Locust Flight

1998 ◽  
Vol 80 (6) ◽  
pp. 3137-3147 ◽  
Author(s):  
Jan-Marino Ramirez
Keyword(s):  
Respiratory Activity ◽  
Respiratory Rhythm ◽  
Quiescent State ◽  
Suboesophageal Ganglion ◽  
Rhythm Generator ◽  
Locust Flight ◽  
Respiratory Network ◽  
Intracellular Stimulation ◽  
Tonic Stimulation ◽  
Stimulation Of

Ramirez, Jan-Marino. Reconfiguration of the respiratory network at the onset of locust flight. J. Neurophysiol. 80: 3137–3147, 1998. The respiratory interneurons 377, 378, 379 and 576 were identified within the suboesophageal ganglion (SOG) of the locust. Intracellular stimulation of these neurons excited the auxillary muscle 59 (M59), a muscle that is involved in the control of thoracic pumping in the locust. Like M59, these interneurons did not discharge during each respiratory cycle. However, the SOG interneurons were part of the respiratory rhythm generator because brief intracellular stimulation of these interneurons reset the respiratory rhythm and tonic stimulation increased the frequency of respiratory activity. At the onset of flight, the respiratory input into M59 and the SOG interneurons was suppressed, and these neurons discharged in phase with wing depression while abdominal pumping movements remained rhythmically active in phase with the slower respiratory rhythm (Fig. 9 ). The suppression of the respiratory input during flight seems to be mediated by the SOG interneuron 388. This interneuron was tonically activated during flight, and intracellular current injection suppressed the respiratory rhythmic input into M59. We conclude that the respiratory rhythm generator is reconfigured at flight onset. As part of the rhythm-generating network, the interneurons in the SOG are uncoupled from the rest of the respiratory network and discharge in phase with the flight rhythm. Because these SOG interneurons have a strong influence on thoracic pumping, we propose that this neural reconfiguration leads to a behavioral reconfiguration. In the quiescent state, thoracic pumping is coupled to the abdominal pumping movements and has auxillary functions. During flight, thoracic pumping is coupled to the flight rhythm and provides the major ventilatory movements during this energy-demanding locomotor behavior.

scholarly journals Efficacy of Tramadol, Low Dose Ketamine and Ondansetron in the Management of Intra-Operative Shivering After Sub Arachnoid Block

2018 ◽  
Vol 4 (1) ◽  
pp. 45-50
Author(s):  
Md Aminul Hasanat ◽  
MM Abdul Wadud ◽  
Abdul Hye ◽  
AKM Akhtaruzzaman ◽  
Lutful Kabir ◽  
...  
Keyword(s):  
Intensive Care ◽  
Respiratory Rate ◽  
Respiratory Depression ◽  
Low Dose ◽  
P Value ◽  
Single Center ◽  
Double Blind ◽  
Randomized Control ◽  
Medical University ◽  
Age Range

Background: Shivering is a common problem faced by an anesthesiologist during per-operative period as well as in post-operative period.Objective: The present study was designed to observe the efficacy of tramadol, low dose ketamine and ondansetron in the management of intra-operative shivering after sub arachnoid block.Methodology: This single center, parallel, double blind randomized control trialwas conducted in the Department of Anaesthesia, Analgesia and Intensive Care Medicine at Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh from July 2007 to June 2009 for a period of two (02) years.Patients undergoing surgery with Sub Arachnoid Block, patients with age range from 18 to 60 years, patients from both sexes and ASA class I and class II were selected as study population.After recruitment each subject was allowed to draw one card and grouped accordingly. Group T: Shivering was treated with tramadol. Group K: Low dose ketamine was used to manage shivering. Group 0: Ondansetron was injected for shivering. The patients was also monitored for complications like nausea, vomiting and respiratory depression (defined as respiratory rate <8/minute). Time taken for cessation of shivering was noted for all groups and all patients were watched for recurrence of shivering.Result: A total of 90 (ninety) patients were enrolled in this study of whom thirty (30) patients were enclosed in each group. Among thirty patients in each group. Group T was effective in 27(90%) patients, group K was effective in 21(70%) patients and group O in 20(66.7%) patients with a p value of 0.075. Statistically, though it is not significant but according to the consideration of percentage, Group T is superior to other two groups. Again recurrence of shivering occurred in one patient in Gr.-T, eight (08) person in Gr.-K and three (03) patient in group Gr.-O indicating a p value of 0.024. This equation reflects the lowest statistically significant recurrence of shivering in Group T than others.Out of thirty patients in each group, nausea or vomiting occurred only in 3 patients of T group (10%) respiratory depression occurred in 10 patients (33.3%) of K group only.Conclusion: The efficacy of tramadol is a better option than low dose ketamine and ondansetron in the management of intra-operative shivering after sub arachnoid block.Journal of National Institute of Neurosciences Bangladesh, 2018;4(1): 45-50

scholarly journals Maturation of the Mammalian Respiratory System

1999 ◽  
Vol 79 (2) ◽  
pp. 325-360 ◽  
Author(s):  
Gérard Hilaire ◽  
Bernard Duron
Keyword(s):  
Respiratory Activity ◽  
Respiratory Rhythm ◽  
Ventrolateral Medulla ◽  
Pacemaker Neurons ◽  
Inhibitory Processes ◽  
Respiratory Rhythmogenesis ◽  
Respiratory Network ◽  
Network Functions

In this review, the maturational changes occurring in the mammalian respiratory network from fetal to adult ages are analyzed. Most of the data presented were obtained on rodents using in vitro approaches. In gestational day 18 (E18) fetuses, this network functions but is not yet able to sustain a stable respiratory activity, and most of the neonatal modulatory processes are not yet efficient. Respiratory motoneurons undergo relatively little cell death, and even if not yet fully mature at E18, they are capable of firing sustained bursts of potentials. Endogenous serotonin exerts a potent facilitation on the network and appears to be necessary for the respiratory rhythm to be expressed. In E20 fetuses and neonates, the respiratory activity has become quite stable. Inhibitory processes are not yet necessary for respiratory rhythmogenesis, and the rostral ventrolateral medulla (RVLM) contains inspiratory bursting pacemaker neurons that seem to constitute the kernel of the network. The activity of the network depends on CO2 and pH levels, via cholinergic relays, as well as being modulated at both the RVLM and motoneuronal levels by endogenous serotonin, substance P, and catecholamine mechanisms. In adults, the inhibitory processes become more important, but the RVLM is still a crucial area. The neonatal modulatory processes are likely to continue during adulthood, but they are difficult to investigate in vivo. In conclusion, 1) serotonin, which greatly facilitates the activity of the respiratory network at all developmental ages, may at least partly define its maturation; 2) the RVLM bursting pacemaker neurons may be the kernel of the network from E20 to adulthood, but their existence and their role in vivo need to be further confirmed in both neonatal and adult mammals.

scholarly journals Opioid-induced respiratory depression: reversal by non-opioid drugs

2014 ◽  
Vol 6 ◽  
Author(s):  
Rutger van der Schier ◽  
Margot Roozekrans ◽  
Monique van Velzen ◽  
Albert Dahan ◽  
Marieke Niesters
Keyword(s):  
Respiratory Depression ◽  
Opioid Drugs

scholarly journals Multi-Level Regulation of Opioid-Induced Respiratory Depression

Physiology ◽  
2020 ◽  
Vol 35 (6) ◽  
pp. 391-404
Author(s):  
Barbara Palkovic ◽  
Vitaliy Marchenko ◽  
Edward J. Zuperku ◽  
Eckehard A. E. Stuth ◽  
Astrid G. Stucke
Keyword(s):  
Respiratory Rate ◽  
Respiratory Depression ◽  
Minute Ventilation ◽  
Direct Effects ◽  
Respiratory Phase ◽  
Multi Level ◽  
Prebotzinger Complex ◽  
Prebötzinger Complex ◽  
Excitatory Drive

Opioids depress minute ventilation primarily by reducing respiratory rate. This results from direct effects on the preBötzinger Complex as well as from depression of the Parabrachial/Kölliker-Fuse Complex, which provides excitatory drive to preBötzinger Complex neurons mediating respiratory phase-switch. Opioids also depress awake drive from the forebrain and chemodrive.

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