Opioids depress breathing through two small brainstem sites

Elife. 2020 Feb 19:9:e52694. doi: 10.7554/eLife.52694.

Abstract

The rates of opioid overdose in the United States quadrupled between 1999 and 2017, reaching a staggering 130 deaths per day. This health epidemic demands innovative solutions that require uncovering the key brain areas and cell types mediating the cause of overdose- opioid-induced respiratory depression. Here, we identify two primary changes to murine breathing after administering opioids. These changes implicate the brainstem's breathing circuitry which we confirm by locally eliminating the µ-Opioid receptor. We find the critical brain site is the preBötzinger Complex, where the breathing rhythm originates, and use genetic tools to reveal that just 70-140 neurons in this region are responsible for its sensitivity to opioids. Future characterization of these neurons may lead to novel therapies that prevent respiratory depression while sparing analgesia.

Keywords: breathing; central pattern generator; human biology; medicine; mouse; neuroscience; opioid respiratory depression; preBötzinger Complex.

Plain language summary

Opioids such as morphine or fentanyl are powerful substances used to relieve pain in medical settings. However, taken in too high a dose they can depress breathing – in other words, they can lead to slow, shallow breaths that cannot sustain life. In the United States, where the misuse of these drugs has been soaring in the past decades, about 130 people die each day from opioid overdose. Pinpointing the exact brain areas and neurons that opioids act on to depress breathing could help to create safer painkillers that do not have this deadly effect. While previous studies have proposed several brain regions that could be involved, they have not been able to confirm these results, or determine which area plays the biggest role. Opioids influence the brain of animals (including humans) by attaching to proteins known as opioid receptors that are present at the surface of neurons. Here, Bachmutsky et al. genetically engineered mice that lack these receptors in specific brain regions that control breathing. The animals were then exposed to opioids, and their breathing was closely monitored. The experiments showed that two small brain areas were responsible for breathing becoming depressed under the influence of opioids. The region with the most critical impact also happens to be where the breathing rhythms originate. There, a small group of 50 to 140 neurons were used by opioids to depress breathing. Crucially, these cells were not necessary for the drugs’ ability to relieve pain. Overall, the work by Bachmutsky et al. highlights a group of neurons whose role in creating breathing rhythms deserves further attention. It also opens the possibility that targeting these neurons would help to create safer painkillers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / adverse effects*
  • Animals
  • Brain Stem / drug effects*
  • Brain Stem / physiology
  • Humans
  • Mice
  • Plethysmography, Whole Body
  • Respiration / drug effects
  • Respiratory Insufficiency / chemically induced*

Substances

  • Analgesics, Opioid