UCSF

Opioids are perhaps the most effective analgesics in medicine. However, between 1999 and 2020, over 500,000 people in the United States died from opioid overdose. This health epidemic demands innovative solutions that will require uncovering the key brain areas and cell types mediating the cause of overdose— opioid-induced respiratory depression. Here, I identify two primary changes to breathing after administering opioids. These changes implicate the brainstem’s breathing circuitry which I confirm by locally eliminating the µ-Opioid receptor. I 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. Meanwhile, in the absence of this basic understanding of the mechanisms mediated opioid respiratory depression, some groups have already moved forward with development of therapeutics with novel biochemical properties they claim will dissociate opioid-like analgesia from effects on breathing. One such approach has been the design of so-called ‘biased agonists’ that signal through some, but not all pathways downstream of the µ-opioid receptor (MOR), the target of morphine and other opioid analgesics. This rationale stems from a study suggesting that MOR-induced ß-arrestin 2 dependent signaling is responsible for opioid respiratory depression, whereas adenylyl cyclase inhibition produces analgesia. To verify this important result that motivated the ‘biased agonist’ approach, I re-examine breathing in ß-arrestin 2-deficient mice and instead find no connection between ß-arrestin 2 and opioid respiratory depression. Put together, this work suggests a new approach to develop safer opioid-like drugs is needed, and that future characterization of the small group of neurons mediating respiratory depression may lead to novel therapies that prevent respiratory side effects while sparing analgesia.