Neuromodulation of respiratory control and potential pharmacotherapy to alleviate respiratory depression

The focus of this thesis is toward understanding the roles played by important neurochemical modulators on respiratory rhythm in physiological and pathophysiological conditions using in vitro and in vivo rodent models and developing a potential drug therapy to alleviate central respiratory depression. Three major studies were undertaken. (1) I determined the actions of GABAA and glycine receptor-mediated chloride conductances on respiratory rhythmogenesis in perinatal rats. That systematic study demonstrates that the transition from excitatory to inhibitory effects of chloride-mediated conductances on respiratory rhythmogenesis occurs at embryonic day 19 in the rat, regulated by the development of chloride co-transporters. I then demonstrated that GABAA receptor-mediated modulation of perinatal respiration is further influenced by neurosteroids. Collectively, those data demonstrate that the modulation of breathing by chloride-mediated conductances via glycine and GABAA receptor activation is determined by the developmental stage and overall balance of negative and positive neurosteroid modulators within respiratory nuclei. (2) I studied central respiratory disorders in a genetic mouse model. I tested necdin-deficient mice, one of a cluster of genes deleted in the neurodevelopmental disorder Prader-Willi syndrome (PWS). Both animal models and children with PWS have apparent respiratory insufficiency during the neonatal period. I demonstrate that the respiratory defect can be explained by abnormal neuronal activities within the putative respiratory rhythm-generating centre. Specifically, the rhythm is unstable with prolonged periods of depression of respiratory rhythmogenesis. Exogenous application of excitatory neuromodulators alleviates slow respiratory rhythms, but some instability of rhythmogenesis persists. These observations may reflect abnormalities of respiratory rhythm-generating neurons and conditioning neuromodulatory drive. (3) My final research project was directed toward developing a novel and clinically relevant pharmacological means of alleviating respiratory depression. I demonstrate that the ampakine class of drugs (by modulating AMPA-type glutamate receptor) counters respiratory depression associated with opioid analgesics, anesthetics and weak endogenous drive. Importantly, the ampakine CX717, which is metabolically stable and safe for human use, can alleviate life-threatening opioid-induced respiratory depression without interfering with analgesia. Thus, CX717 could potentially improve the safety margin for administering powerful analgesic agents, which would provide a valuable tool for clinicians to optimize pain management in patients.