Intermittent respiratory stimulation with doxapram induces phrenic motor plasticity

Abstract

Intermittent hypoxia can induce a persistent increase in phrenic motor output via a central neural mechanism. Here we explored a pharmacological alterative to hypoxia as a tool for triggering phrenic motor plasticity. Specifically, we hypothesized that persistent increases in efferent phrenic burst activity can be evoked via systemic delivery of a low‐dose of doxapram – a drug which can robustly stimulate phrenic activity due to activation of carotid chemoafferents. Anesthetized, vagotomized, paralyzed and mechanically‐ventilated rats were given intravenous doxapram either intermittently (3 × 2mg/kg) or as a single dose (2mg/kg or 6mg/kg). A persistent increase in phrenic burst amplitude was evoked by intermittent doxapram (161 ± 27% baseline at 60 min post‐injection, p<0.05 vs. sham injection and time control), but not by the single dose (104 ± 13% baseline). The acute phrenic response was substantially reduced in carotid‐denervated rats (120 ± 3% baseline compared to 165 ± 9% baseline in animals with intact carotid nerves, p<0.05) confirming that doxapram acts primarily via the carotid chemoreceptors. Since doxapram is an FDA approved drug and commonly used as a respiratory stimulant, it may be a viable alternative or supplement to hypoxia for targeted induction of respiratory neuroplasticity in neurological conditions such as spinal cord injury.Support: Craig H. Neilsen Foundation #220521 (MSS), 1R01NS080180–01A1 (DDF), NIH1R21HL104294–01 (DDF)