title: Methylxanthine reversal of opioid-induced respiratory depression in the neonatal rat: mechanism and location of action.
abstract: Methylxanthines like caffeine and theophylline have long been used to treat apnea of prematurity. Despite their success in stimulating neonatal breathing, their mechanism of action remains poorly understood. Methylxanthines can act as both non-specific adenosine receptor antagonists and inhibitors of cAMP-dependent phosphodiesterases, sarcoplasmic/endoplasmic 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 consensus is that methylxanthines stimulate the respiratory centers of the brainstem. Here we used the in situ neonatal rat working heart-brainstem preparation and the ex vivo neonatal rat 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 effects of methylxanthine therapy are likely mediated centrally, predominantly via inhibition of cAMP-dependent phosphodiesterase-4.
authors.affiliation: Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors.forename: E V
authors.initials: EV
authors.lastname: Mosca
authors.affiliation: Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors.forename: P
authors.initials: P
authors.lastname: Ciechanski
authors.affiliation: Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors.forename: A
authors.initials: A
authors.lastname: Roy
authors.affiliation: Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors.forename: E C
authors.initials: EC
authors.lastname: Scheibli
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
authors.forename: K
authors.initials: K
authors.lastname: Ballanyi
authors.affiliation: Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada T2N 4N1. Electronic address: wilsonr@ucalgary.ca.
authors.forename: R J A
authors.initials: RJ
authors.lastname: Wilson
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001049:Apnea / Q000188:drug therapy / Q000503:physiopathology; D001933:Brain Stem / Q000187:drug effects* / Q000502:physiology; D002344:Carotid Body / Q000187:drug effects* / Q000502:physiology; D000697:Central Nervous System Stimulants; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology; D011799:Quinazolines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000187:drug effects*; D013805:Theobromine / Q000031:analogs & derivatives / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology*; D046509:Tissue Culture Techniques; D014230:Triazoles / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000697:Central Nervous System Stimulants; D011799:Quinazolines; D014230:Triazoles; D014970:Xanthines; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C008514:methylxanthine; C057837:3,7-dimethyl-1-propargylxanthine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D013805:Theobromine; C052410:9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine
keywords: Apnea; Carotid body; Methylxanthine; Neonate; Prematurity