How do opioids make us stop breathing?

Opioids, such as morphine and fentanyl, are two-faced drugs. They can be used in the most compassionate way, as the most effective way to relieve pain. But they are also highly dangerous, causing long-term addiction if not instant death when taken in excess. How can one substance do so much to help and harm at the same time?

Each day ~130 people in the United States die from the suppression of their breathing by opioids. To combat this pandemic, it is critical to identify the central or peripheral cites, as well as the key neurons within, that opioids act upon to slow breathing. Recently, we definitively showed that opioids suppress breathing by acting upon just two small clusters of brainstem neurons, and of these two, the most critical is the breathing pacemaker node. Within this node, just ~70-140 neurons (<5% of neurons) are responsible to opioid sensitivity. Importantly, these neurons have no impact upon pain relieving property of opioids. We are now keen to understand how such a small number of neurons could so drastically slow the breathing rhythm, how they are involved in general breathing, and if endogenous opioids use them to regulate breathing.

At this moment, exciting pharmacological approaches are being developed to create opioid like compounds that provide analgesia without pain. It is believed they do so by restricting the opioid receptor signaling to just a subset of pathways. This work stems from a pioneering study on the molecule ß-arrestin 2 which reported that deletion of this gene prevented opioids from suppressing breathing while still providing pain relief. Given the important impact of this discovery, we have attempted and failed to replicate this study. Our work shows that it still remains an important task to identify the molecular mechanism(s) that opioids use to suppress breathing as well as how these new, promising therapeutics provide analgesia without respiratory depression.