Fentanyl effects on respiratory neuron activity in the dorsolateral pons

Saunders, Sandy E; Baekey, David M.; Levitt, Erica S.

doi:10.1152/jn.00113.2022

Cited by 10 publications

(9 citation statements)

References 71 publications

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“…Neurons were further grouped by discharge pattern, recognizing that separation into many subgroups decreases statistical power while summation of different neuron types into one group may confound subtype-specific remifentanil effects. Neuron subtypes matched those described in similar studies (Krolo et al, 2005;Smith et al, 2007;Rybak et al, 2008;Segers et al, 2008;Zuperku et al, 2019;Saunders et al, 2022), and especially studies of functional connections between PRG and preBötC/BötC (Rybak et al, 2008;Segers et al, 2008;Zuperku et al, 2019) to allow for functional interpretation of the results.…”

Section: Neuron Classificationmentioning

confidence: 73%

Changes in pontine and preBötzinger/Bötzinger complex neuronal activity during remifentanil-induced respiratory depression in decerebrate dogs

et al. 2023

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Introduction:In vivo studies using selective, localized opioid antagonist injections or localized opioid receptor deletion have identified that systemic opioids dose-dependently depress respiratory output through effects in multiple respiratory-related brainstem areas.Methods: With approval of the subcommittee on animal studies of the Zablocki VA Medical Center, experiments were performed in 53 decerebrate, vagotomized, mechanically ventilated dogs of either sex during isocapnic hyperoxia. We performed single neuron recordings in the Pontine Respiratory Group (PRG, n = 432) and preBötzinger/Bötzinger complex region (preBötC/BötC, n = 213) before and during intravenous remifentanil infusion (0.1–1 mcg/kg/min) and then until complete recovery of phrenic nerve activity. A generalized linear mixed model was used to determine changes in Fn with remifentanil and the statistical association between remifentanil-induced changes in Fn and changes in inspiratory and expiratory duration and peak phrenic activity. Analysis was controlled via random effects for animal, run, and neuron type.Results: Remifentanil decreased Fn in most neuron subtypes in the preBötC/BötC as well as in inspiratory (I), inspiratory-expiratory, expiratory (E) decrementing and non-respiratory modulated neurons in the PRG. The decrease in PRG inspiratory and non-respiratory modulated neuronal activity was associated with an increase in inspiratory duration. In the preBötC, the decrease in I-decrementing neuron activity was associated with an increase in expiratory and of E-decrementing activity with an increase in inspiratory duration. In contrast, decreased activity of I-augmenting neurons was associated with a decrease in inspiratory duration.Discussion: While statistical associations do not necessarily imply a causal relationship, our data suggest mechanisms for the opioid-induced increase in expiratory duration in the PRG and preBötC/BötC and how inspiratory failure at high opioid doses may result from a decrease in activity and decrease in slope of the pre-inspiratory ramp-like activity in preBötC/BötC pre-inspiratory neurons combined with a depression of preBötC/BötC I-augmenting neurons. Additional studies must clarify whether the observed changes in neuronal activity are due to direct neuronal inhibition or decreased excitatory inputs.

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Section: Neuron Classificationmentioning

confidence: 73%

Changes in pontine and preBötzinger/Bötzinger complex neuronal activity during remifentanil-induced respiratory depression in decerebrate dogs

et al. 2023

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“…Inhibitory transmission in the medullary rhythm generator influences respiratory rate in the case of phasic inhibition or causes sustained apnea in the case of prolonged inhibition ( Baertsch et al, 2018 ; Cregg et al, 2017 ; Sherman et al, 2015 ). We have recently found that inspiratory dorsolateral pontine neurons are silenced by fentanyl, whereas expiratory neurons are not ( Saunders et al, 2022 ). An intriguing possibility is that opioid-insensitive pontine neurons, which have continued activity during opioid exposure, send prolonged input to inhibitory neurons in the ventrolateral medulla to promote apnea, perhaps using pathways overlapping those involved in apneas evoked by excitation of certain parts of the KF area ( Saunders and Levitt, 2020 ; Dutschmann and Dick, 2012 ; Dutschmann and Herbert, 2006 ).…”

Section: Discussionmentioning

confidence: 99%

Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms

Bateman

Levitt

2023

eLife

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Opioids depress breathing by inhibition of inter-connected respiratory nuclei in the pons and medulla. Mu opioid receptor (MOR) agonists directly hyperpolarize a population of neurons in the dorsolateral pons, particularly the Kölliker-Fuse (KF) nucleus, that are key mediators of opioid-induced respiratory depression. However, the projection target and synaptic connections of MOR-expressing KF neurons are unknown. Here, we used retrograde labeling and brain slice electrophysiology to determine that MOR-expressing KF neurons project to respiratory nuclei in the ventrolateral medulla, including the pre-Bötzinger complex (preBötC) and rostral ventral respiratory group (rVRG). These medullary projecting, MOR-expressing dorsolateral pontine neurons express FoxP2 and are distinct from calcitonin gene-related peptide-expressing lateral parabrachial neurons. Furthermore, dorsolateral pontine neurons release glutamate onto excitatory preBötC and rVRG neurons via monosynaptic projections, which is inhibited by presynaptic opioid receptors. Surprisingly, the majority of excitatory preBötC and rVRG neurons receiving MOR-sensitive glutamatergic synaptic input from the dorsolateral pons are themselves hyperpolarized by opioids, suggesting a selective opioid-sensitive circuit from the KF to the ventrolateral medulla. Opioids inhibit this excitatory pontomedullary respiratory circuit by three distinct mechanisms-somatodendritic MORs on dorsolateral pontine and ventrolateral medullary neurons and presynaptic MORs on dorsolateral pontine neuron terminals in the ventrolateral medulla-all of which could contribute to opioid-induced respiratory depression.

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“…Fentanyl-associated deficits in respiratory patterning result from a reduced activity of pontine inspiratory neurons, while apnea is observed after the loss of all phasic pontine activity and sustained tonic expiratory neuron activity. Using in situ rat preparations of the arterially perfused dorsolateral pons, neurons were categorized based on their respiratory-associated discharge pattern after incubation with an apneic fentanyl concentration [ 16 ]. When exposed to fentanyl, the inspiratory neurons were silenced or exhibited a reduced firing frequency, while the expiratory neurons only reduced their tonic firing frequency.…”

Section: Neurorespiratory Effects Of Fentanyl and Analogsmentioning

confidence: 99%

Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs—Lessons from Animal Studies

et al. 2023

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In 2020, fentanyl and its analogs contributed to ~65% of drug-attributed fatalities in the USA, with a threatening increasing trend during the last ten years. These synthetic opioids used as potent analgesics in human and veterinary medicine have been diverted to recreational aims, illegally produced and sold. Like all opioids, central nervous system depression resulting from overdose or misuse of fentanyl analogs is characterized clinically by the onset of consciousness impairment, pinpoint miosis and bradypnea. However, contrasting with what observed with most opioids, thoracic rigidity may occur rapidly with fentanyl analogs, contributing to increasing the risk of death in the absence of immediate life support. Various mechanisms have been proposed to explain this particularity associated with fentanyl analogs, including the activation of noradrenergic and glutamatergic coerulospinal neurons and dopaminergic basal ganglia neurons. Due to the high affinities to the mu-opioid receptor, the need for more elevated naloxone doses than usually required in morphine overdose to reverse the neurorespiratory depression induced by fentanyl analogs has been questioned. This review on the neurorespiratory toxicity of fentanyl and analogs highlights the need for specific research focused on these agents to better understand the involved mechanisms of toxicity and develop dedicated strategies to limit the resulting fatalities.

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Fentanyl effects on respiratory neuron activity in the dorsolateral pons

Cited by 10 publications

References 71 publications

Changes in pontine and preBötzinger/Bötzinger complex neuronal activity during remifentanil-induced respiratory depression in decerebrate dogs

Changes in pontine and preBötzinger/Bötzinger complex neuronal activity during remifentanil-induced respiratory depression in decerebrate dogs

Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms

Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs—Lessons from Animal Studies

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