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Antagonistic modulation of spontaneous neural network activities in isolated newborn rat brainstem preparations by opioids and methylxanthines Open Access


Other title
calcium imaging
locus coeruleus
preBotzinger Complex
Type of item
Degree grantor
University of Alberta
Author or creator
Panaitescu, Bogdan Alexandru
Supervisor and department
Ballanyi, Klaus (Physiology Department, University of Alberta)
Examining committee member and department
Smith, Peter (Pharmacology Department, University of Alberta)
Funk, Gregory (Physiology Department, University of Alberta)
Del Negro, Christopher (Department of Applied Science, The College of William and Mary)
Gosgnach, Simon (Physiology Department, University of Alberta)
Department of Physiology

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Apnea of prematurity is a common problem among the infants born before term pregnancy. Administration of respiratory stimulating drugs methylxanthines is the most frequent therapy, often in combination with the use of intubation. Opioids are used to reduce the pain associated with intubation, although they can depress breathing by acting on inspiratory neural networks located in the lower medulla, such as pre-Bötzinger Complex (preBötC). The aim of this thesis was to study the effects of methylxanthines and opioids on the respiratory active network preBötC and to compare the findings with those in the spontaneously active newborn network, locus coeruleus (LC). In a first project, it was found that novel 400 μm thick slices with centered preBötC showed stable inspiratory rhythm for >5 h in a solution with 5-6 mM K+ and 1 mM Ca2+. Elevated Ca2+ concentrations (1.5-2 mM Ca2+) blocked rhythm without postsynaptic changes in membrane potential or input resistance, while concentrations lower than 0.75 mM evoked seizure-like discharges. Similar to elevated Ca2+, the μ-opioid agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) abolished preBötC neuron bursting with minor postsynaptic effects, which was reversed by methylxanthines without changes on membrane properties. The same methylxanthine dose evoked non-respiratory discharges in spinal inspiratory motor networks, while the preBötC remained largely unaffected. Based on these findings it was studied whether spontaneous bursting of LC networks in horizontal brainstem slices was perturbed by low millimolar methylxanthine. The results showed that the LC is similarly resistant to methylxanthines which can evoke a depolarization that reverses the DAMGO-induced hyperpolarization. Ca2+ imaging in either preBötC or LC revealed that DAMGO lowers Ca2+ baseline in neurons and abolishes their rhythm-related Ca2+ rises, which are restored by low millimolar methylxanthines without a hypothesized store-mediated effect. Neither DAMGO nor methylxanthines affected Ca2+ in silent small cells, likely representing astrocytes. These novel electrophysiological and optical findings provide the basis for future studies dedicated to analyze whether the lack of obvious postsynaptic membrane effects of both opioids and methylxanthines are an indication of a major role of presynaptic inhibition, which potentially underlies also the strong preBötC inhibition by raised extracellular calcium.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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