Role of the pre-Bötzinger complex in respiratory rhythm generation in vivo: influence of respiratory network drive

We have previously demonstrated that microinjection of DL-homocysteic acid (DLH), a glutamate analog, into the pre-Bötzinger complex (pre-BötC) can produce either phasic or tonic excitation of phrenic nerve discharge. Our initial findings were obtained during hyperoxic normocapnia; thus, the influence of respiratory network drive, including intrinsic pre-BötC neuronal excitability, on the DLH-induced modulation of phrenic motor output requires clarification. We, therefore, examined the effects of chemical stimulation of the pre-BötC during increased respiratory network drive elicited by hypercapnia, hypoxia (ie, peripheral chemoreflex), or focal pre-BötC tissue acidosis in chloralose-anesthetized, vagotomized, mechanically ventilated cats. For these experiments, we selected sites in which unilateral microinjection of DLH into the pre-BötC during hyperoxic normocapnia (PaCO₂ = 37–43 mmHg) produced a non-rhythmic tonic excitation of phrenic nerve discharge. During hypercapnia (PaCO₂ = 59.7 ± 2.8 mmHg; n = 17), similar microinjection produced excitation in which respiratory rhythmic oscillations were superimposed on varying levels of tonic discharge. A similar pattern of modulation was observed in response to microinjection of DLH into the pre-BötC during normocapnic hypoxia (PaCO₂ = 38.5 ± 3.7; PaO₂ = 38.4 ± 4.4; n = 8) and during focal pre-BötC tissue acidosis (n = 7). Further, during increased respiratory network drive, these DLH-induced respiratory rhythmic oscillations had an increased frequency compared to the preinjection baseline frequency of phrenic bursts (P < 0.05). These findings demonstrate that tonic inspiratory motor activity evoked by chemical stimulation of the pre-BötC is influenced by and integrates with modulation of respiratory network drive mediated by input from both central and peripheral chemoreceptors, as well as focal pre-BötC CO₂/H⁺ chemosensitivity.