The study, published in the journal Proceedings of the National Academy of Sciences, demonstrates how activating specific opioid receptors in these neurons results in opioid-induced respiratory depression, or OIRD, the disrupted breathing associated with overdose deaths.

Additionally, it demonstrates how blocking these receptors can reverse OIRD.

In 2020, the United States saw over 93,000 overdose deaths, with an estimated 60% attributed to opioids such as fentanyl. Opioids work by binding to opioid receptors on nerve cells (neurons) and inhibiting their activity. Currently, naloxone is the only medication known to reverse an opioid overdose. However, naloxone has limitations, including a short duration that necessitates repeated administration. Additionally, it acts systemically, inhibiting opioid receptors throughout the body, including those that regulate pain.

To develop more precise strategies for OIRD rescue, the researchers set out to identify breathing neurons in the brain that also contain opioid receptors. The new study identified a population of neurons that express a specific type of opioid receptor (the mu opioid receptor) and are located in the brainstem breathing modulation centre; they then defined these neurons’ role in OIRD.

They found that mice genetically engineered to lack opioid receptors in these neurons did not experience respiratory depression when exposed to morphine, whereas control mice did. Additionally, the researchers showed that, in the absence of opioids, stimulating these receptors in control mice resulted in OIRD symptoms.

The researchers then investigated ways to revert the process by treating overdosed mice with chemical compounds that target other receptors on the same neurons that serve in the opposite manner as the opioid receptor (activating rather than inhibiting them).

According to the study, the team discovered four distinct chemical compounds that successfully activated these neurons and restored breathing rate during OIRD.

The researchers now intend to investigate whether additional cell types play a role in OIRD. Additionally, additional research would examine the relationship between breathing regulation and pain perception in the brain, which could pave the way for the development of more targeted treatments for OIRD.

“We hope to explain the pain-breathing segregation at the molecular or microcircuit level,” said the study authors.

“By doing that, we can try to restore breathing without touching analgesic effects of opioids.”