Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network

Elife. 2021 Aug 17:10:e67523. doi: 10.7554/eLife.67523.

Abstract

The analgesic utility of opioid-based drugs is limited by the life-threatening risk of respiratory depression. Opioid-induced respiratory depression (OIRD), mediated by the μ-opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBötzinger Complex (preBötC). To unravel the cellular- and network-level consequences of MOR activation in the preBötC, MOR-expressing neurons were optogenetically identified and manipulated in transgenic mice in vitro and in vivo. Based on these results, a model of OIRD was developed in silico. We conclude that hyperpolarization of MOR-expressing preBötC neurons alone does not phenocopy OIRD. Instead, the effects of MOR activation are twofold: (1) pre-inspiratory spiking is reduced and (2) excitatory synaptic transmission is suppressed, thereby disrupting network-driven rhythmogenesis. These dual mechanisms of opioid action act synergistically to make the normally robust inspiratory rhythm-generating network particularly prone to collapse when challenged with exogenous opioids.

Keywords: Oprm1; breathing; mouse; neuroscience; opioid; pre-bӧtzinger complex; respiratory depression; rhythm-generation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics, Opioid / adverse effects*
  • Animals
  • Female
  • Male
  • Mice
  • Mice, Transgenic
  • Receptors, Opioid, mu / genetics*
  • Receptors, Opioid, mu / metabolism
  • Respiratory Center / drug effects*
  • Respiratory Insufficiency / chemically induced
  • Respiratory Insufficiency / physiopathology*
  • Synaptic Transmission / drug effects*
  • Synaptic Transmission / physiology

Substances

  • Analgesics, Opioid
  • Oprm protein, mouse
  • Receptors, Opioid, mu