Methylxanthine reversal of opioid-evoked inspiratory depression via phosphodiesterase-4 blockade.
Hypothetic mechanisms for respirogenic methylxanthine actions include blockade of adenosine receptors or phosphodiesterase-4 (PDE4) in inspiratory pre-Bötzinger complex (preBötC) networks. Here, we studied this by analyzing stimulating caffeine and theophylline actions on mu-opioid-depressed inspiratory-related rhythm in the ventrolateral aspect of rat brainstem slices. The methylxanthines restored DAMGO (0.5-1 microM) depressed rhythm only at >1mM, which is approximately 10-fold higher than selective for adenosine receptors. Adenosine receptor blockers did neither counter DAMGO inhibition nor change control rhythm, similar to adenosine (0.1-2.5 mM). The specific PDE4 blocker rolipram (5 microM) restored DAMGO-depressed rhythm incompletely, but effectively reversed similar inhibition by clinical mu-agonist (fentanyl, 0.1 microM). At 0.25 microM, rolipram boosted incomplete recovery by 1 mM theophylline of DAMGO-depressed rhythm. Findings indicate that methylxanthines excite rhythmogenic preBötC networks via blockade of cAMP dependent PDE4 and suggest that specific PDE4 inhibitors (plus low methylxanthine doses) stimulate breathing effectively. We discuss why methylxanthine doses for preBötC stimulation need to be higher than those for respirogenic effects in vivo.
Ruangkittisakul
Araya
A
Department of Physiology & Perinatal Research Centre, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada.
Ballanyi
Klaus
K
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002110:Caffeine / Q000494:pharmacology; D004594:Electrophysiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005283:Fentanyl / Q000037:antagonists & inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000187:drug effects; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000517:prevention & control*; D012143:Respiratory Physiological Phenomena / Q000187:drug effects; D020889:Rolipram / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology*
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000701:Analgesics, Opioid; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D017450:Receptors, Opioid, mu; D014970:Xanthines; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C008514:methylxanthine; D002110:Caffeine; D013806:Theophylline; D020889:Rolipram; D005283:Fentanyl