Hypercapnia potentiates the action of μ‐opioid receptor agonists on synaptic transmission in the preBötzinger complex

Abstract

Acute respiratory depression is a leading cause of mortality in individuals who overdose on opiates. Moreover, the magnitude of respiratory depression is variable and unpredictable, making the use of opiates particularly dangerous. Opiates can blunt the hypercapnic respiratory response, yet the precise mechanisms underlying this phenomenon are unclear. The objective of this study was to determine how hypercapnia influences the action of the μ‐opioid receptor agonist, DAMGO, on rhythmogenesis and synaptic transmission within the preBötC. Electrophysiological recordings were made from rhythmic transverse brainstem slices (mice, P6‐P12) during the following conditions: (1) normocapnia (90% O2,5% CO2; 25mM NaHCO3); (2) hypercapnic acidosis (HA: 90% O2, 10% CO2; 25mM NaHCO3). In normocapnia, 25nM DAMGO suppressed the frequency of rhythmogenesis by 24 ± 11%. HA exaggerated the effect of 25nM DAMGO reducing frequency by 66 ± 10%. Similarly, HA augmented the effects of morphine (7.5nM) on the preBötC. Recordings of evoked excitatory postsynaptic potentials shows that HA exaggerates the suppression of glutamatergic drive to preBötC neurons. Moreover, during normocapnia 25nM DAMGO fully suppressed rhythmogenesis in the presence of 20μM CPP, a NMDA receptor antagonist. These data indicate that HA augments the effects of μ‐opioid agonists on glutamatergic synaptic transmission in the preBötC.