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It has long been known that opioid overdose deaths are caused by disturbed breathing, but the actual mechanism by which these drugs suppress breathing was not understood. Now, a new study by scientists at Salk has identified a group of neurons in the brainstem that play a key role in this process.
The results, published on June 8 in the journal Proceedings of the National Academy of Sciences, show how triggering specific receptors in these neurons causes opioid-induced respiratory depression, or OIRD, the disturbed breathing that causes overdose deaths. It also shows how blocking these receptors can cause OIRD to reverse.
“The underlying mechanism as to why opiates slow down and lower the respiratory rate has not been fully characterized,” says lead researcher Sung Han, assistant professor at the Clayton Foundation’s laboratories in Salk for peptide biology. “This knowledge can be a stepping stone to better treatment options for OIRDs.”
The United States recorded more than 93,000 overdose deaths in 2020, of which about 60% were attributed to opioids like fentanyl. Opioids work by binding to proteins in nerve cells (neurons) called opioid receptors and subsequently inhibiting their activity. Currently, naloxone is the only drug known to block the effects of opioids and reverse an overdose. But naloxone has limitations, including a short duration that requires it to be administered multiple times. It also works systemically, blocking opioid receptors throughout the body, including those that control pain.
To develop strategies to save OIRD with more specificity, Han’s team set out to search for respiratory neurons in the brain that also carry opioid receptors. In the new study, researchers have identified a group of neurons that express a certain type of opioid receptor (the mu opioid receptor) and are located in the brainstem’s respiratory modulation center; they then characterized the role of these neurons in OIRD.
They found that mice genetically engineered not to have opioid receptors in these neurons did not have their breathing disturbed when exposed to morphine, as did mice in the control group. The researchers also found that, without introducing opioids, stimulation of these receptors in control mice caused symptoms of OIRD.
The team then looked for ways to reverse the process by treating the overdosed mice with chemicals targeted at other receptors on the same neurons, which play a role opposite to that of the opioid receptor (by activating them rather than by inhibiting them).
“We discovered four different chemical compounds that successfully activated these neurons and brought back the respiratory rate during OIRD,” said first author Shijia Liu, a graduate student of the Han lab. The recovery in the overdosed mice was close to 100 percent, which surprised the team.
The researchers then plan to examine whether other cell groups play a role in OIRD as well. Further study would also examine the link between the regulation of breathing and the perception of pain in the brain, potentially opening the door to the development of more targeted treatments for OIRD.
“We hope to explain painful respiratory segregation at the molecular or microcircuit level,” says Han, Pioneer Fund Development chair. “By doing this, we can try to restore breathing without affecting the pain relieving effects of opioids. “
Reference:
Liu S, Kim DI, Oh TG et al. Neural basis of opioid-induced respiratory depression and its rescue. PNAS. 2021; 118 (23). doi: 10.1073 / pnas.2022134118
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