Countering by methylxanthines of opioid‐evoked depression of spontaneous network oscillations in locus coeruleus of newborn rat brain slices

Abstract

Treatment of (preterm) infants with opioids for analgesia can inhibit medullary respiratory networks controling breathing. Countering such opioid‐evoked and spontaneous apneas of prematurity with theophylline or caffeine can elicit seizures. Here, we studied in 400 μm thick horizontal brain slices from 0–4 days‐old rats whether these methylxanthines also counter opioid depression and evoke hyperexcitability in neural networks of locus coeruleus. Suction electrode recording revealed synchronized regular neuronal population bursting in locus coeruleus at 0.5–5 Hz which was disrupted neither by 10 mM theophylline, 10 mM caffeine nor GABAA receptor blockade (bicuculline, 25 μM). At 25 nM, the μ‐opioid receptor agonist DAMGO transformed fast oscillations into slower group bursts whereas 100–250 nM DAMGO abolished rhythm. At 1 mM, theophylline in 250 nM DAMGO reactivated slow rhythm whereas 2.5–10 mM restored faster oscillations. Block of oscillations by 250 nM DAMGO led to concomitant 10–25 mV hyperpolarization and a fall of Fluo‐4‐AM imaged cytosolic Ca2+ baseline in locus coeruleus neurons which were (partially) reversed by 10 mM theophylline. Findings indicate that methylxanthines do not cause seizure in locus coeruleus but counter opioid‐evoked depression of these networks with involvement of postsynaptic mechanisms.