A new strategy suggests that opioid receptors outside the brain play a bigger role in overdose than previously thought and may hold the key to eliminating the severe withdrawal symptoms caused by naloxone, one of the most effective treatments for opioid overdose.
Opioids work by binding to receptors throughout the body, but in the case of an overdose, binding in regions of the brain that control breathing and heartrate cause both essential functions to slow down or even stop.
Known as opioid-induced respiratory depression, this scenario is dangerous and can lead to death if not quickly treated. Making matters worse, synthetic opioids like fentanyl more easily cross into the brain and have a stronger binding affinity than other opioids.
In recent years, fentanyl use has substantially increased the risks of overdose among people with opioid use disorder.
Naloxone reverses opioid induced respiratory depression by entering the brain and binding to the same receptors as opioids, but with a higher affinity. This blocks the opioids from attaching to the receptors, preventing the dangerous slowdown of breathing and heart rate.
“While naloxone is generally effective in reversing opioid-induced respiratory depression, the precipitated withdrawal can be extremely unpleasant for individuals recovering from an overdose,” said Brain Ruyle, a postdoctoral research associate at Washington University in St. Louis in a press release. These withdrawal symptoms can cause patients to be anxious, sometimes making them difficult to treat or even leading them back to drug-seeking behaviours.
“We know fentanyl binds to opioid receptors abundant in brain regions controlling breathing, but these receptors are also present in the peripheral nervous system throughout the body,” Ruyle said. This led the team to speculate they may be involved in overdose and could provide a new avenue for treatment.
Could a better option be out there?
Ruyle and his colleagues decided to test whether a naloxone derivative, which cannot enter the brain, has any ability to treat overdose symptoms.
Using a rodent model, the team gave the derivative called naloxone methiodide to rats that had received various doses of fentanyl, and monitored heart rate, breathing, and oxygen levels.
Surprisingly, the treatment prevented respiratory depression, just like naloxone, showing that these peripheral receptors are more involved in overdose related breathing problems than expected.
Next, they tested whether naloxone methiodide could reverse overdose and opioid-induced respiratory depression.
In this experiment, the drug was administered after the rodents received either a 20 or 50 microgram per kilogram dose. At the lower of the two doses, naloxone methiodide or naloxone restored breathing to baseline levels. At the higher dose, however, more naloxone methiodide was needed to restore breathing. Importantly, no naloxone methiodide was detected in the brain, confirming that the overdose symptoms were halted by treating only peripheral opioid receptors.
Finally, to see whether the naloxone derivative caused the same problematic side effects as naloxone, the group tested the rats aversion to naloxone after treatment.
For this experiment, rodents were treated with fentanyl in their usual home cage and receive the naloxone or naloxone methiodide in a separate treatment cage. Afterward, the researchers monitor how averse the rats are to spending time in the treatment cage.
This is a standard test in animal studies where animals like rodents associate experiences with the environments they occurred in and will avoid the cages where they experienced a negative experience or stimulus. For rats treated with the derivative, there was no aversion, and the rodents did not avoid the cage where they received treatment. The opposite was true for the rodent’s given naloxone, who spent significantly less time in the naloxone associated cages.
More work needed, but a promising start
These results are preclinical and require significant follow-up, but they are promising.
“In this study, we show that blocking peripheral opioid receptors with naloxone methiodide in rodents sufficiently prevents and reverses fentanyl-induced cardiorespiratory depression and low oxygen levels without causing aversive behaviours, as compared to naloxone,” said the study’s senior author, Jose A. Morón, in the same press release.
The team has some theories as to how the peripheral receptors are involved in overdose, such as fentanyl causing aberrant signalling to the respiratory centres within the brain. However, the exact mechanism is yet to be determined.
For the millions of Americans and others around the world suffering from opioid use disorder and who are at risk of overdose, this work may lead to a more palatable treatment.
“Our findings provide evidence that blocking peripheral opioid receptors may be a potential new strategy to reverse opioid-induced respiratory depression without inducing withdrawal, anxiety and aversion, all of which can contribute to further relapse in drug-seeking behaviours,” said Morón.
Reference: Brian C Ruyle, et al. Peripheral opioid receptor antagonism alleviates fentanyl-induced cardiorespiratory depression and is devoid of aversive effects, eLife (2024). DOI: 10.7554/eLife.104469.1
Feature image: Two milligrams of fentanyl ona pencil tip – a lethal dose for most people. Image credit: United States Drug Enforcement Administration (DEA), Public domain, via Wikimedia Commons
