Accepted Manuscript Title: Methylxanthine reversal of opioid-induced respiratory depression in the neonatal rat: Mechanism and location of action Author: E.V. Mosca P. Ciechanski A. Roy E.C. Scheibli K. Ballanyi R.J.A. Wilson PII: DOI: Reference:
S1569-9048(14)00149-9 http://dx.doi.org/doi:10.1016/j.resp.2014.06.002 RESPNB 2317
To appear in:
Respiratory Physiology & Neurobiology
Received date: Revised date: Accepted date:
22-2-2014 3-6-2014 3-6-2014
Please cite this article as: Mosca, E.V., Ciechanski, P., Roy, A., Scheibli, E.C., Ballanyi, K., Wilson, R.J.A.,Methylxanthine reversal of opioid-induced respiratory depression in the neonatal rat: Mechanism and location of action, Respiratory Physiology and Neurobiology (2014), http://dx.doi.org/10.1016/j.resp.2014.06.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Methylxanthine reversal of opioid-induced respiratory depression in
ip t
the neonatal rat: Mechanism and location of action
Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada. T2N 4N1 Department of Physiology, University of Alberta, Edmonton, Alberta, Canada. T6G 2S2
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Corresponding author:
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1
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Mosca, E.V.1, Ciechanski, P.1, Roy, A.1, Scheibli, E.C.1, Ballanyi, K.2, & Wilson, R.J.A.1
Dr. Richard J.A. WILSON Dept. of Physiology and Pharmacology Hotchkiss Brain Institute Faculty of Medicine University of Calgary 3330 Hospital Drive NW Calgary, Alberta, Canada T2N 4N1 email: [email protected] tel: 403 220 8460
1
Page 1 of 38
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ABSTRACT
Methylxanthines like caffeine and theophylline have long been used to treat apnea of
cr
prematurity. Despite their success in stimulating neonatal breathing, their mechanism of action
us
remains poorly understood. Methylxanthines can act as both non-specific adenosine receptor antagonists and inhibitors of cAMP-dependent phosphodiesterases, sarcoplasmic/endoplasmic
an
reticulum calcium ATPases or receptor-coupled anion channels, depending on the dose used. Though there is evidence for methylxanthine action at the level of the carotid body, the
M
consensus is that methylxanthines stimulate the respiratory centres of the brainstem. Here we
d
used the in situ neonatal rat working heart-brainstem preparation and the ex vivo neonatal rat
te
carotid body preparation to test the hypothesis that methylxanthines act at the level of the carotid body. We conclude that although the neonatal carotid body has active adenosine receptors, the
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effects of methylxanthine therapy are likely mediated centrally, predominantly via inhibition of cAMP-dependent phosphodiesterase-4.
Running Head: Methylxanthine reversal of opioid-induced respiratory depression
2
Page 2 of 38
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INTRODUCTION
Apnea of prematurity (AOP) occurs in over 85% of neonates born at less than 34 weeks gestation
cr
(Boutourline-Young & Smith, 1950; Fenner, Schalk, Hoenicke, Wendenburg, & Roehling, 1973)
us
and in virtually all neonates born at less than 28 weeks gestation (Eichenwald, Aina, & Stark, 1997; Hofstetter, Legnevall, Herlenius, & Katz-Salamon, 2008). AOP can result in decreases in
an
arterial O2 saturation of 40%, constituting an acute concern for neonatal survival and detrimental long-term effects (Upton, Milner, & Stokes, 1991). Clinical care of neonates with AOP
M
frequently involves administering methylxanthines, a group of closely related compounds that
te
& Finer, 2003).
d
includes caffeine and theophylline (i.e., 1,3-dimethylxanthine), to stimulate breathing (Graham
Ac ce p
Off-target effects of methylxanthine administration include changes in coronary blood flow and heart rate (Bünger, Haddy, & Gerlach, 1975; Carnielli et al., 2000), increased likelihood of seizure activity (Panaitescu et al., 2013), and at high doses, altered brainstem development in preterm infants and decreased survival during anoxia (Thurston et al. 1978). Therefore, minimal doses of caffeine and theophylline should be used in infants experiencing AOP. Determining the mechanism by which methylxanthines stimulate breathing could aid in this objective and lead to the development of more specific drugs.
3
Page 3 of 38
At the cellular level, methylxanthines may act through one or more independent mechanisms: at concentrations
S1569-9048(14)00149-9 http://dx.doi.org/doi:10.1016/j.resp.2014.06.002 RESPNB 2317
To appear in:
Respiratory Physiology & Neurobiology
Received date: Revised date: Accepted date:
22-2-2014 3-6-2014 3-6-2014
Please cite this article as: Mosca, E.V., Ciechanski, P., Roy, A., Scheibli, E.C., Ballanyi, K., Wilson, R.J.A.,Methylxanthine reversal of opioid-induced respiratory depression in the neonatal rat: Mechanism and location of action, Respiratory Physiology and Neurobiology (2014), http://dx.doi.org/10.1016/j.resp.2014.06.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Methylxanthine reversal of opioid-induced respiratory depression in
ip t
the neonatal rat: Mechanism and location of action
Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada. T2N 4N1 Department of Physiology, University of Alberta, Edmonton, Alberta, Canada. T6G 2S2
Ac ce p
Corresponding author:
te
d
M
an
2
us
1
cr
Mosca, E.V.1, Ciechanski, P.1, Roy, A.1, Scheibli, E.C.1, Ballanyi, K.2, & Wilson, R.J.A.1
Dr. Richard J.A. WILSON Dept. of Physiology and Pharmacology Hotchkiss Brain Institute Faculty of Medicine University of Calgary 3330 Hospital Drive NW Calgary, Alberta, Canada T2N 4N1 email: [email protected] tel: 403 220 8460
1
Page 1 of 38
ip t
ABSTRACT
Methylxanthines like caffeine and theophylline have long been used to treat apnea of
cr
prematurity. Despite their success in stimulating neonatal breathing, their mechanism of action
us
remains poorly understood. Methylxanthines can act as both non-specific adenosine receptor antagonists and inhibitors of cAMP-dependent phosphodiesterases, sarcoplasmic/endoplasmic
an
reticulum calcium ATPases or receptor-coupled anion channels, depending on the dose used. Though there is evidence for methylxanthine action at the level of the carotid body, the
M
consensus is that methylxanthines stimulate the respiratory centres of the brainstem. Here we
d
used the in situ neonatal rat working heart-brainstem preparation and the ex vivo neonatal rat
te
carotid body preparation to test the hypothesis that methylxanthines act at the level of the carotid body. We conclude that although the neonatal carotid body has active adenosine receptors, the
Ac ce p
effects of methylxanthine therapy are likely mediated centrally, predominantly via inhibition of cAMP-dependent phosphodiesterase-4.
Running Head: Methylxanthine reversal of opioid-induced respiratory depression
2
Page 2 of 38
ip t
INTRODUCTION
Apnea of prematurity (AOP) occurs in over 85% of neonates born at less than 34 weeks gestation
cr
(Boutourline-Young & Smith, 1950; Fenner, Schalk, Hoenicke, Wendenburg, & Roehling, 1973)
us
and in virtually all neonates born at less than 28 weeks gestation (Eichenwald, Aina, & Stark, 1997; Hofstetter, Legnevall, Herlenius, & Katz-Salamon, 2008). AOP can result in decreases in
an
arterial O2 saturation of 40%, constituting an acute concern for neonatal survival and detrimental long-term effects (Upton, Milner, & Stokes, 1991). Clinical care of neonates with AOP
M
frequently involves administering methylxanthines, a group of closely related compounds that
te
& Finer, 2003).
d
includes caffeine and theophylline (i.e., 1,3-dimethylxanthine), to stimulate breathing (Graham
Ac ce p
Off-target effects of methylxanthine administration include changes in coronary blood flow and heart rate (Bünger, Haddy, & Gerlach, 1975; Carnielli et al., 2000), increased likelihood of seizure activity (Panaitescu et al., 2013), and at high doses, altered brainstem development in preterm infants and decreased survival during anoxia (Thurston et al. 1978). Therefore, minimal doses of caffeine and theophylline should be used in infants experiencing AOP. Determining the mechanism by which methylxanthines stimulate breathing could aid in this objective and lead to the development of more specific drugs.
3
Page 3 of 38
At the cellular level, methylxanthines may act through one or more independent mechanisms: at concentrations
