Opioid drugs are key adjuncts in the management of acute and chronic pain. However, they depress respiration in therapeutic doses, limiting their effectiveness, and cause fatal respiratory arrest in overdose. At present there is very little information about the cellular and neural network disturbances which underlie opioid respiratory depression. This in vivo investigation will identify mechanisms through which opioids disturb excitability and rhythm in several types of medullary respiratory neurons that control depth and rate of respiration. In adult decerebrate cats of either sex (1), Receptor-selective opioids will be pressure-microinjected into regions of the medulla which are known to influence depth and rate of respiration, and their effects on motor discharges in hypoglossal (HGN), recurrent laryngeal (RLN) and phrenic (PN) nerves will be measured. The results will reveal how these sites contribute to opioid depression of respiratory depth and rate, how they influence upper airway resistance in the presence of opioids, and the functional significance of different subtypes of opioid receptors. (2), Effects of opioids applied by microiontophoresis to medullary Inspiratory, Post-Inspiratory and Expiratory neurons will be measured and analyzed with intra- and extracellular recording methods. Responses related to specific subtypes of opioid receptor will be identified by applying receptor-selective agonists and antagonists to each type of neuron. This research will reveal how opioids and their receptors alter excitability in functionally important cell types and thus contribute to reductions in depth and rate of breathing. (3), A novel approach for reversing opioid-induced depression of the respiratory network based on activating D1-dopamine receptors on respiratory neurons to increase intracellular cyclic AMP will be investigated. In some experiments, A D1-dopamine receptor agonist will be applied by microiontophoresis to respiratory neurons to determine whether it reverses opioid-evoked depression of cell excitability. In others, receptors on respiratory neurons and network interneurons will be activated by administering the D1-agonist intravenously, and its effectiveness will be judged from its ability to reverse depression of HGN, RLN and PN discharges produced by i.v. injections of opioids. This project will thus identify sites, cells and receptors in the medulla where endogenous opioids modulate respiration and where opiate drugs depress breathing. It will also test a new method that may alleviate opioid-induced depression of respiration without affecting analgesia, and counteract respiratory depression by overdose of opioids.
