Caffeine Reversal of Opioid-Evoked and Endogenous Inspiratory Depression in Perinatal Rat En Bloc Medullas and Slices

Abstract

Caffeine counters endogenous or drug-evoked depression of breathing in (preterm) infants. Despite its common clinical use, little is known on central nervous mechanisms of its stimulatory respiratory action. We show that millimolar concentrations of caffeine are needed in perinatal rat en bloc medullas and medullary slices for stimulation of fictive inspiratory rhythms that were either endogenously slow in fetuses or depressed by prostagandins or opioids. Findings suggests that caffeine blocks phospodiesterase-4 thus raising cAMP in rhythmogenic pre-Bötzinger complex (preBötC) networks and/or cells driving the inspiratory preBötC.

Loss of Atoh1 from neurons regulating hypoxic and hypercapnic chemoresponses causes neonatal respiratory failure in mice

“…Caffeine treatment, along with glutamate and substance P, can stimulate endogenous, slow respiratory rhythms in rats ( Ruangkittisakul et al, 2010 ); this is thought to be the mechanism by which caffeine reduces apneas of prematurity in newborn infants ( Aranda et al, 1977 ; Natarajan et al, 2007 ). Caffeine drives this excitation mainly by acting as an antagonist to the A1 adenosine receptor that inhibits respiratory frequency ( Koos et al, 2001 ).…”

Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding

“…24; D1 dopamine receptors, Refs. 134-136), 2) Methylxanthines, caffeine, and theophylline given to counter apneas of prematurity (137)(138)(139), and 3) Phosphodiesterase 4 (PDE4) inhibitors (rolipram) (140)(141)(142). Each of these manipulations would be expected to counter cAMP decreases due canonical Ga i/o signaling downstream of activated MOR (143).…”