Substance P Neurons in the Brain's Breathing Center Can Reverse Opioid-Induced Breathing Failure | Research

The takeaway

Stimulating substance P-expressing neurons in the brain's breathing center promoted rhythmic breathing and overcame opioid-induced respiratory depression in mice.

Overcame opioid respiratory depression
Optogenetic activation of substance P neurons in the preBötzinger Complex restored breathing in mice experiencing opioid-induced respiratory failure — the primary cause of death in opioid overdose.

What the researchers found

Tachykinin precursor 1 (Tac1) neurons in the preBötzinger Complex (preBötC) — the brain's breathing rhythm generator — promote rhythmic breathing when stimulated. Using optogenetics, researchers showed that activating these substance P-expressing neurons stimulated breathing in both anesthetized and freely moving mice, triggered locomotion, and critically, overcame opioid-induced respiratory depression. These findings establish Tac1 neurons as a key excitatory population with dual roles in breathing and motor behavior.

Why it matters

Opioid-induced respiratory depression is the primary cause of death in opioid overdose. The discovery that stimulating substance P-expressing neurons in the breathing center can overcome opioid-induced breathing suppression identifies a potential new approach to preventing overdose deaths. This connects the well-known neuropeptide substance P to a critical unmet medical need.

The numbers in context

Tac1-cre mouse model · ChETA channelrhodopsin-2 optogenetics · preBötC stimulation · promoted breathing in anesthetized + freely moving mice · overcame opioid respiratory depression · triggered locomotion

How the study worked

Researchers used Tac1-cre transgenic mice with adeno-associated virus delivering excitatory channelrhodopsin-2 (ChETA) targeted to the preBötzinger Complex. They combined histological characterization, optogenetic stimulation, respiratory measurements, and behavioral assays to assess the effects of activating Tac1 neurons on breathing patterns, motor behavior, and opioid-induced respiratory depression in both anesthetized and freely moving animals.

Who was studied

Tac1-cre transgenic mice (anesthetized and freely moving) with optogenetic preBötC manipulation

What this study cannot tell us

This is a mouse study using optogenetic tools that are not directly translatable to human clinical use. The preBötC is a small, deep brainstem structure that would be difficult to target therapeutically in humans. The study focused on acute stimulation effects; long-term or repeated stimulation effects were not assessed. The relative contributions of substance P signaling versus glutamatergic signaling from these dual-phenotype neurons were not fully separated.

How to read the evidence

This is a well-executed preclinical neuroscience study using state-of-the-art optogenetic techniques in transgenic mice. The convergent evidence from anesthetized and freely moving preparations is strong, but the optogenetic approach is not directly translatable to human therapy.

When this study was published

Published in 2023 in eLife, this study reflects current neuroscience approaches to understanding breathing regulation and has significant implications for the ongoing opioid crisis.

The bigger picture

The opioid crisis kills over 100,000 people annually in the US alone, primarily through respiratory depression. While naloxone (Narcan) reverses overdose by blocking opioid receptors, it also reverses pain relief and can trigger withdrawal. This study suggests an alternative approach: directly stimulating breathing circuits via substance P neurons without reversing the opioid's other effects. It adds substance P to a growing list of neuropeptides being investigated as potential tools for respiratory rescue.

Questions still open

Could substance P receptor agonists be developed as drugs to stimulate breathing during opioid overdose without reversing analgesia?
Do humans have the same Tac1 neuron population in their preBötzinger Complex, and would it respond similarly?
Could this approach be combined with naloxone to provide more complete respiratory rescue during opioid overdose?

Common questions

How could this help with opioid overdose?

Opioid overdose kills primarily by suppressing the brain's breathing circuits. This study shows that substance P-producing neurons in the breathing center can be activated to restart breathing even when opioids are suppressing it. While the optogenetic technology used isn't practical for human treatment, the finding suggests that drugs targeting substance P receptors in this brain region could potentially rescue breathing during overdose.

What is the preBötzinger Complex?

The preBötzinger Complex (preBötC) is a tiny cluster of neurons deep in the brainstem that acts as the pacemaker for breathing. It generates the rhythmic nerve signals that drive every breath we take. Damage or suppression of the preBötC — as happens during opioid overdose — can cause breathing to stop completely, which is why understanding and being able to stimulate these neurons is so important.

Read the original research

Medullary tachykinin precursor 1 neurons promote rhythmic breathing.

eLife, 12

View on PubMed ↗Publisher’s paper ↗

Citation

Rousseau, Jean-Philippe; Furdui, Andreea; Silveira Scarpellini, Carolina da; Horner, Richard L; Montandon, Gaspard. (2023). Medullary tachykinin precursor 1 neurons promote rhythmic breathing.. eLife, 12. https://doi.org/10.7554/eLife.85575