Research Project
10279580
Project Summary The recent increase in overdose deaths, fueled by an increase in opioid addiction and the availability of highly potent opioids like fentanyl has turned opioid-induced respiratory depression (OIRD) into a public health problem. In addition, OIRD has long been recognized as a major risk factor in the perioperative period where it can require intensified postoperative management or, on rare occasions, result in hypoxic injury. Total opioid dose and the concomitant use of sedative drugs like benzodiazepines are significantly associated with an increased risk of OIRD. Consequently, there is great urgency to develop drugs that can alleviate OIRD without reversing analgesia or causing withdrawal. Over the past 20 years, development of respiratory stimulating drugs has been guided by the central dogma that the preBötzinger Complex (preBötC) is the brainstem site that controls respiratory rate and pattern generation, that OIRD is due to an effect on the preBötC, and that to counteract OIRD drugs must stimulate the preBötC. However, drugs that were developed in animals to stimulate breathing through effects on the preBötC were not sufficiently effective in humans. Based on our published and preliminary data we propose a novel paradigm where the respiratory pattern is generated in the preBötC but two separate brainstem areas, the Parabrachial Nucleus/ Kölliker-Fuse Complex (PBN/KF), and the caudal medullary raphe (CMR) contribute excitatory drive to preBötC neurons responsible for switching in particular from expiration to inspiration and thus determine respiratory rate. These areas are also highly sensitive to clinical opioid doses. Injection of the opioid antagonist naloxone into these areas completely prevented OIRD, even at high opioid doses. The goal of our study is to determine whether stimulation of neurons in the PBN/KF and CMR can overcome OIRD and whether there are limits to this effect. We will use our adult, in vivo decerebrate rabbit preparation, which allows to investigate opioid- and other drug effects on single neurons and in functionally identified cell nuclei without baseline anesthesia and with neuronal networks and physiological reflexes intact. We will measure how much opioids and other sedatives depress neuronal function in and synaptic inputs to the PBN/KF, CMR, and preBötC. We will then test how much AMPA and NMDA receptor modulators, i.e., drugs that enhance the function of excitatory AMPA and NMDA receptors, increase the activity of PBN/KF, CMR, and preBötC neurons, whether this can offset the depression from opioids and sedatives and whether the effect is limited at high opioid and sedative doses. The results will significantly improve our insights into the neuronal mechanisms of drug-induced respiratory depression and into potential therapeutic approaches and limitations.
