Caffeine Abolishes TrkB Receptor‐Dependent Respiratory‐Related Spinal Motor Facilitation in Isolated Neonatal Rat Brainstem‐Spinal Cords In Vitro

Abstract

Caffeine is the main treatment for apnea of prematurity because it stimulates breathing, reduces duration of respiratory support, and increases infant survival. Caffeine has multiple neuronal effects, but it is a well‐established adenosine A2a receptor (A2aR) antagonist. In adult rats, A2aR blockade increases the magnitude of intermittent hypoxia‐induced, TrkB receptor‐dependent, long‐term facilitation of phrenic motor output. In neonates, it is not known whether caffeine blocks A2aRs and enhances TrkB receptor‐induced facilitation of respiratory motor output. To test this question, neonatal (P0‐P3) rat brainstem‐spinal cords were isolated and respiratory‐related motor output recorded from C4‐C5 ventral spinal roots. Bath‐applied dihydroxyflavone (DHF, TrkB receptor agonist, 5–10 μM, 9‐min, n=22) increased respiratory motor burst amplitude by 13 ± 3% relative to baseline at 75 min following drug application, whereas vehicle dimethylsulfoxide‐treated time controls decreased burst amplitude by 11 ± 4% relative to baseline (n=15; p<0.001). A background caffeine application (50–250 μM; 15 min) that overlapped a DHF application (5–10 μM, 9 min) abolished DHF‐induced spinal motor facilitation (burst amplitude was decreased by 7 ± 4% relative to baseline at 75 min). The lack of DHF‐induced spinal motor facilitation with caffeine pretreatment could be due to decreased endogenous signaling in neonatal rat A2aRs (i.e., little or no crosstalk inhibition), or other caffeine effects, such as phosphodiesterase inhibition. If TrkB‐dependent spinal motor facilitation is beneficial in neonates, then caffeine administration may compromise one compensatory mechanism during apnea of prematurity.Support or Funding InformationSupported by: NS085226 (JJW), HL105511 (TLB)