Cellular, molecular, and integrative physiology mechanisms underlying opioid-induced respiratory depression

• Grant number: 22/09734-6
• Support Opportunities: Scholarships abroad - Research
• Start date: July 03, 2023
• End date: July 02, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Thiago dos Santos Moreira
• Grantee: Thiago dos Santos Moreira
• Host Investigator: Jan-Marino Ramirez
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Seattle Children'S Research Institute, United States

Abstract

The opioid epidemic claims more than 50,000 lives every year in North America and contributes to a significant drop in overall life expectancy worldwide. The primary cause of death associated with opioid-based analgesics and drugs of abuse is opioid-induced respiratory depression (OIRD). Although the mortality risk increases in a dose-dependent manner, opioid use is particularly dangerous because it is unpredictable. Many conditions increase the vulnerability to opioids, including sleep-disordered breathing, which is very common among opioid users. Opioids cause respiratory depression and terminal apnea by inhibiting rhythmogenic networks within the ventrolateral medulla. This project has 2 aims to explore the medullary mechanisms, particularly those located in the parafacial respiratory group underlying OIRD. Aim 1 employs a variety of electrophysiological, pharmacological, and optogenetic approaches in vitro and in vivo to explore how opioids inhibit the inspiratory rhythmogenic network. This opioid-sensitive network forms a column that dynamically extends beyond the well-known preBotzinger complex, a circuit essential for breathing. Aim 2 will obtain horizontal slices from this rhythmogenic column to dissect the pre-and postsynaptic mechanisms that are responsible for the cessation of inspiratory activity and how the parafacial region could contribute to restore breathing activity. This project introduces novel concepts of respiratory rhythmogenesis and describes multiple mechanisms of opioid actions, which could explain why opioid respiratory depression is so unpredictable. We test how opioid modulation is sensitized by hypercapnic conditions and chronic intermittent hypoxia, both conditions are often experienced by opioid users. The proposed research may lead to a better understanding of the mechanisms underlying the mortality and morbidity associated with the opioid crisis. (AU)