Dose-dependent Respiratory Depression by Remifentanil in the Rabbit Parabrachial Nucleus/Kölliker–Fuse Complex and Pre-Bötzinger Complex

2021 ◽  
Author(s):  
Barbara Palkovic ◽  
Jennifer J. Callison ◽  
Vitaliy Marchenko ◽  
Eckehard A. E. Stuth ◽  
Edward J. Zuperku ◽  
...  
Keyword(s):  
Respiratory Rate ◽  
Respiratory Depression ◽  
Receptor Agonist ◽  
Parabrachial Nucleus ◽  
Respiratory Drive ◽  
Remifentanil Infusion ◽  
Opioid Receptor Agonist ◽  
Bötzinger Complex ◽  
Dose Dependent ◽  
Partial Reversal

Background Recent studies showed partial reversal of opioid-induced respiratory depression in the pre-Bötzinger complex and the parabrachial nucleus/Kölliker–Fuse complex. The hypothesis for this study was that opioid antagonism in the parabrachial nucleus/Kölliker–Fuse complex plus pre-Bötzinger complex completely reverses respiratory depression from clinically relevant opioid concentrations. Methods Experiments were performed in 48 adult, artificially ventilated, decerebrate rabbits. The authors decreased baseline respiratory rate ~50% with intravenous, “analgesic” remifentanil infusion or produced apnea with remifentanil boluses and investigated the reversal with naloxone microinjections (1 mM, 700 nl) into the Kölliker–Fuse nucleus, parabrachial nucleus, and pre-Bötzinger complex. In another group of animals, naloxone was injected only into the pre-Bötzinger complex to determine whether prior parabrachial nucleus/Kölliker–Fuse complex injection impacted the naloxone effect. Last, the µ-opioid receptor agonist [d-Ala,2N-MePhe,4Gly-ol]-enkephalin (100 μM, 700 nl) was injected into the parabrachial nucleus/Kölliker–Fuse complex. The data are presented as medians (25 to 75%). Results Remifentanil infusion reduced the respiratory rate from 36 (31 to 40) to 16 (15 to 21) breaths/min. Naloxone microinjections into the bilateral Kölliker–Fuse nucleus, parabrachial nucleus, and pre-Bötzinger complex increased the rate to 17 (16 to 22, n = 19, P = 0.005), 23 (19 to 29, n = 19, P < 0.001), and 25 (22 to 28) breaths/min (n = 11, P < 0.001), respectively. Naloxone injection into the parabrachial nucleus/Kölliker–Fuse complex prevented apnea in 12 of 17 animals, increasing the respiratory rate to 10 (0 to 12) breaths/min (P < 0.001); subsequent pre-Bötzinger complex injection prevented apnea in all animals (13 [10 to 19] breaths/min, n = 12, P = 0.002). Naloxone injection into the pre-Bötzinger complex alone increased the respiratory rate to 21 (15 to 26) breaths/min during analgesic concentrations (n = 10, P = 0.008) but not during apnea (0 [0 to 0] breaths/min, n = 9, P = 0.500). [d-Ala,2N-MePhe,4Gly-ol]-enkephalin injection into the parabrachial nucleus/Kölliker–Fuse complex decreased respiratory rate to 3 (2 to 6) breaths/min. Conclusions Opioid reversal in the parabrachial nucleus/Kölliker–Fuse complex plus pre-Bötzinger complex only partially reversed respiratory depression from analgesic and even less from “apneic” opioid doses. The lack of recovery pointed to opioid-induced depression of respiratory drive that determines the activity of these areas. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals Opioid-induced Respiratory Depression Is Only Partially Mediated by the preBötzinger Complex in Young and Adult Rabbits In Vivo

2015 ◽  
Vol 122 (6) ◽  
pp. 1288-1298 ◽  
Author(s):  
Astrid G. Stucke ◽  
Justin R. Miller ◽  
Ivana Prkic ◽  
Edward J. Zuperku ◽  
Francis A. Hopp ◽  
...  
Keyword(s):  
Respiratory Rate ◽  
Respiratory Depression ◽  
Respiratory Rhythm ◽  
Respiratory Drive ◽  
Phase Duration ◽  
Homocysteic Acid ◽  
Opioid Receptor Agonist ◽  
Prebotzinger Complex ◽  
Prebötzinger Complex

Abstract Background: The preBötzinger Complex (preBC) plays an important role in respiratory rhythm generation. This study was designed to determine whether the preBC mediated opioid-induced respiratory rate depression at clinically relevant opioid concentrations in vivo and whether this role was age dependent. Methods: Studies were performed in 22 young and 32 adult New Zealand White rabbits. Animals were anesthetized, mechanically ventilated, and decerebrated. The preBC was identified by the tachypneic response to injection of d,l-homocysteic acid. (1) The μ-opioid receptor agonist [d-Ala2,N-Me-Phe4,Gly-ol]-enkephalin (DAMGO, 100 μM) was microinjected into the bilateral preBC and reversed with naloxone (1 mM) injection into the preBC. (2) Respiratory depression was achieved with intravenous remifentanil (0.08 to 0.5 μg kg−1 min−1). Naloxone (1 mM) was microinjected into the preBC in an attempt to reverse the respiratory depression. Results: (1) DAMGO injection depressed respiratory rate by 6 ± 8 breaths/min in young and adult rabbits (mean ± SD, P < 0.001). DAMGO shortened the inspiratory and lengthened the expiratory fraction of the respiratory cycle by 0.24 ± 0.2 in adult and young animals (P < 0.001). (2) During intravenous remifentanil infusion, local injection of naloxone into the preBC partially reversed the decrease in inspiratory fraction/increase in expiratory fraction in young and adult animals (0.14 ± 0.14, P < 0.001), but not the depression of respiratory rate (P = 0.19). PreBC injections did not affect respiratory drive. In adult rabbits, the contribution of non-preBC inputs to expiratory phase duration was larger than preBC inputs (3.5 [−5.2 to 1.1], median [25 to 75%], P = 0.04). Conclusions: Systemic opioid effects on respiratory phase timing can be partially reversed in the preBC without reversing the depression of respiratory rate.

scholarly journals Opioid microinjection into raphe magnus modulates cardiorespiratory function in mice and rats

2009 ◽  
Vol 297 (5) ◽  
pp. R1400-R1408 ◽  
Author(s):  
Kevin M. Hellman ◽  
Scott J. Mendelson ◽  
Marco A. Mendez-Duarte ◽  
James L. Russell ◽  
Peggy Mason
Keyword(s):  
Heart Rate ◽  
Respiratory Depression ◽  
Lethal Effect ◽  
Respiratory Drive ◽  
Sinus Arrhythmia ◽  
Mu Opioid ◽  
Cardiorespiratory Function ◽  
Opioid Receptor Agonist ◽  
Raphe Magnus ◽  
Rats And Mice

The raphe magnus (RM) participates in opioid analgesia and contains pain-modulatory neurons with respiration-related discharge. Here, we asked whether RM contributes to respiratory depression, the most prevalent lethal effect of opioids. To investigate whether opioidergic transmission in RM produces respiratory depression, we microinjected a mu-opioid receptor agonist, DAMGO, or morphine into the RM of awake rodents. In mice, opioid microinjection produced sustained decreases in respiratory rate (170 to 120 breaths/min), as well as heart rate (520 to 400 beats/min). Respiratory sinus arrhythmia, indicative of enhanced parasympathetic activity, was prevalent in mice receiving DAMGO microinjection. We performed similar experiments in rats but observed no changes in breathing rate or heart rate. Both rats and mice experienced significantly more episodes of bradypnea, indicative of impaired respiratory drive, after opioid microinjection. During spontaneous arousals, rats showed less tachycardia after opioid microinjection than before microinjection, suggestive of an attenuated sympathetic tone. Thus, activation of opioidergic signaling within RM produces effects beyond analgesia, including the unwanted destabilization of cardiorespiratory function. These adverse effects on homeostasis consequent to opioid microinjection imply a role for RM in regulating the balance of sympathetic and parasympathetic tone.

Neuropeptide FF exerts pro- and anti-opioid actions in the parabrachial nucleus to modulate food intake

2003 ◽  
Vol 285 (5) ◽  
pp. R1046-R1054 ◽  
Author(s):  
Danielle M. Nicklous ◽  
Kenny J. Simansky
Keyword(s):  
Food Intake ◽  
Opioid Receptor ◽  
Receptor Agonist ◽  
Parabrachial Nucleus ◽  
Sprague Dawley ◽  
Neuropeptide Ff ◽  
Opioid Receptor Agonist ◽  
Sprague Dawley Rats ◽  
Μ Opioid Receptor ◽  
High Concentrations

Neurons that synthesize the morphine modulatory peptide neuropeptide FF (NPFF; Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) densely innervate the parabrachial nucleus (PBN), an area implicated in regulating food intake. We analyzed opioid-related actions of NPFF in feeding in adult male Sprague-Dawley rats. Unilateral infusion of 2 nmol/0.5 μl of the μ-opioid receptor agonist [d-Ala2,NMe-Phe4,glycinol5]enkephalin (DAMGO) into the lateral PBN increased 4-h food intake from 0.7 ± 0.1 to 3.3 ± 0.3 g. NPFF (1.25-5.0 nmol) prevented this hyperphagic μ-opioidergic action. In rats fed after 4-h deprivation (baseline = 12.3 ± 0.3 g/2 h), 5 nmol of NPFF did not alter and larger doses (10 and 20 nmol) actually increased food intake (+36, 54%). Twenty nanomoles also elevated intake of freely feeding rats (from 0.7 ± 0.1 to 5.1 ± 1.0 g/4 h). The opioid receptor blocker naloxone (10 nmol) antagonized this increase. These data reveal both pro- and anti-opioid actions of NPFF in the PBN to modulate feeding. The mechanisms for the opposite actions of low and high concentrations of this neuropeptide in parabrachial regulation of food intake remain to be determined.

scholarly journals μ-Opioid receptor agonist injections into the presumed pre-Bötzinger complex and the surrounding region of awake goats do not alter eupneic breathing

2009 ◽  
Vol 107 (5) ◽  
pp. 1591-1599 ◽  
Author(s):  
K. L. Krause ◽  
S. E. Neumueller ◽  
B. D. Marshall ◽  
T. Kiner ◽  
J. M. Bonis ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Receptor Agonist ◽  
Minute Ventilation ◽  
Pulmonary Ventilation ◽  
Respiratory Rhythm ◽  
Blood Gases ◽  
Arterial Blood ◽  
Opioid Receptor Agonist ◽  
Bötzinger Complex ◽  
Μ Opioid Receptor

Opioids are clinically important in the alleviation of pain. An undesirable side effect of opioids is depression of breathing. Data from isolated preparations suggest this effect is due to attenuation of discharge activity of neurons in the pre-Bötzinger complex (preBötzC), a medullary area with respiratory rhythmogenic properties. The purpose of this study was to examine how [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), a μ-opioid receptor agonist, affected breathing after injection into the presumed preBötzC of the adult awake goat. We hypothesized that DAMGO would cause breathing to decrease and become irregular when injected into the presumed preBötzC and the surrounding region of the conscious animal. We further hypothesized that ventilatory sensitivity to CO2 and hypoxia would be blunted after the injection of DAMGO. Microtubules were bilaterally implanted into the presumed preBötzC of 10 adult female goats. After recovery from the surgery, DAMGO (0.5–10 μl, 1 nM–10 μM) was injected into the presumed preBötzC during the awake state. DAMGO had no effect on pulmonary ventilation [inspiratory minute ventilation (V̇i)], respiratory rhythm and pattern, the activation pattern of inspiratory and expiratory muscles, or arterial blood gases during eupneic breathing conditions ( P > 0.10). However, DAMGO attenuated ( P < 0.05) the evoked increase in breathing frequency when inspired CO2 was increased, and DAMGO attenuated the V̇i response to reduction of inspired O2 to 10.8% ( P < 0.05). We conclude that our data do not provide support for the concept that in awake mammals opioid depression of breathing is due to a directed action of opioids on preBötzC neurons.

Lateralized Periodic Discharges During Remifentanil Infusion

2021 ◽  
pp. 155005942110106
Author(s):  
Janaarththanan Sakathevan ◽  
Karthik Somasundaram ◽  
Sandra C. Chinyere ◽  
Cristina Rodríguez-Viña ◽  
David Martín-López
Keyword(s):  
Receptor Agonist ◽  
Remifentanil Infusion ◽  
Mechanically Ventilated ◽  
Neurointensive Care Unit ◽  
Periodic Discharges ◽  
Opioid Receptor Agonist ◽  
Μ Opioid Receptor ◽  
First Time ◽  
The Brain ◽  
Eeg Pattern

Lateralized periodic discharges (LPDs) are a common electroencephalographic (EEG) pattern in the neurointensive care unit setting. LPDs are typically observed in association with acute structural lesions of the brain with different etiologies. There are no reports describing a link between the occurrence of LPDs and the administration of remifentanil. Remifentanil is a rapid-acting pure μ-opioid receptor agonist, which is indicated to provide analgesia and sedation in mechanically ventilated patients in intensive care units. We present a case of an 84-year-old man with neuroglycopenia who developed LPDs while sedated with remifentanil. We report, for the first time, a potential relationship between remifentanil and the induction of LPDs.

Does caffeine improve respiratory rate during remifentanil target controlled infusion sedation? A case report in endoscopic sedation

2017 ◽  
Vol 13 (2) ◽  
pp. 125 ◽  
Author(s):  
Fabio Sbaraglia, MD ◽  
Mariella De Riso, MD ◽  
Maria Elena Riccioni, MD ◽  
Guido Costamagna, MD ◽  
Maria Sammartino, MD
Keyword(s):  
Respiratory Rate ◽  
Protective Role ◽  
Respiratory Center ◽  
Respiratory Drive ◽  
Remifentanil Infusion ◽  
Impaired Patient ◽  
Target Controlled Infusion ◽  
Therapeutic Colonoscopy ◽  
Positive Effect ◽  
Neonatal Apnea

Sedation for endoscopic procedures may be challenging when facing patients with high risk. Traditional techniques, as propofol or meperidine/midazolam administration, cannot ensure an adequate level of safety and efficacy for these patients. Remifentanil infusion is a common alternative, but the incidence of apneic events does not allow achieving safely a good level of analgesia. To overcome with this issue, the authors borrowed suggestions from other medical fields. The clinical practice has recognized a wide utility of methylxanthines (caffeine, theophylline, etc). The positive effect of caffeine on the airways function is known and in the treatment of neonatal apnea, it works as direct stimulant of central respiratory center. Furthermore, preclinical studies suggest that methylxanthines could have a protective role on the opioids inhibition of the bulbar-pontine respiratory center. As described in this report, the authors observed that, also when apnea has been induced by remifentanil, caffeine is able to restore the respiratory rate. The authors present the management of a respiratory impaired patient scheduled for a therapeutic colonoscopy. Our sedation was focused on the match between remifentanil in target controlled infusion and intravenous caffeine, like an “expresso to wake-up” the respiratory drive.

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