New Delhi: A study published in Nature journal reports the discovery of a new compound called “368” that works alongside existing medication such as naloxone to reduce opioid addiction. This chemical compound acts as a negative modulator that attaches to the pain relief receptor (µ-opioid) and reduces side-effects of opioid use, while not entirely negating the pain relief aspect of it. Naloxone is one of the most common drugs currently used to treat opioid overdose.
Researchers from Stanford University, Washington University, and the University of Florida conducted this study, published on 3 July, by looking at a ‘library’ of chemical compounds with their DNA sequences to identify those that work well with the µ-opioid receptor in its inactive state, so as not to mess with the pain relief function of strong opioids like fentanyl.
Data from the National Institute on Drug Abuse shows that opioid overdose deaths in the US almost doubled from 49,860 in 2019 to 81,806 in 2022. The authors of the study suggest that the process, which they used to find compound ‘368’, could prove to be effective for future research in therapeutics that can modulate opioid overdoses with fewer withdrawal symptoms and manage pain without the risk of overdose from pain relief medication.
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How does opioid overdose occur?
Opioids are a class of drugs that act on the pain in different parts of the body, and examples of these drugs include morphine, fentanyl and codeine. The way opioids function is that they attach themselves to pain receptors in the body, such as the µ-opioid receptor. When the receptor binds to an opioid such as fentanyl, it gets activated and then sends signals that lead to pain relief in different parts of the body.
However, the issue is that drugs like fentanyl and morphine also have extreme side-effects which include causing addiction and respiratory illnesses such as breathing issues. The binding of fentanyl in pain receptors in the brain makes it used to the drug, after which our body requires higher and higher doses of it to have the same effect.
The Nature study also explained how fentanyl is often mixed with other drugs and sold illegally since it is a cheap alternative to recreational drugs. High doses of fentanyl also act as a depressant for the respiratory system in the body by binding with the central nervous system — effects include reduced breathing, decrease in the depth of each breath and a slower response to increased CO2 levels in the body.
Compound 368’s effects
There are some drugs, most common of which is naloxone, that work to reverse the effects of opioid overdose. Naloxone is used for its rapid action that restores normal breathing and consciousness when a patient is suffering from opioid overdose, but it needs to be taken in large doses and repeatedly to overcome the impact of strong opioids.
The way naloxone works is by acting as a competitive antagonist, which means it binds to the same active site of receptor where the opioid has bound itself, and it rapidly reverses the action of opioids. This reversal is what leads to restoration of normal breathing and bodily functions in patients of opioid overdose.
The active site of the µ-opioid receptor is known as the orthosteric site, while other sites on the receptor that aren’t active are called allosteric sites.
The Nature study that compound 368 chose to focus on drugs that work on these alternative allosteric sites — they don’t actively stop the action of the opioid but rather modulate its effects by binding to inactive sites on the same opioid receptor.
In studies conducted with mice, the authors showed that compound ‘368’ does exactly that: it is a negative allosteric modulator (NAM) that basically binds to the inactive part of the µ-opioid receptor and enhances the effect of naloxone. The study found that in the presence of ‘368’, naloxone’s effectiveness in reversing an opioid overdose increased by 7.6 times. This cooperation with naloxone led the authors of the study to put forth the idea that compound ‘368’ could be used in combination with existing opioid overdose reversal drugs.
The authors also measured the effects of compound ‘368’ on the withdrawal symptoms that arise from opioid overdose.
They found that symptoms like stool inconsistency were significantly reduced when compound ‘368’ and naloxone were administered together to the mice, as opposed to just a high dose of naloxone.
The drug was administered and studied only on animals. However, the researchers suggest that the overall process of drugs that act on inactive sites of the opioid receptor could be revolutionary to the field of therapeutic medicine. As displayed in compound ‘368’, they not only enhance the potency of existing drugs like naloxone, they also have side benefits that selectively target opioid receptors and modulate the effects of opioids.
(Edited by Zinnia Ray Chaudhuri)
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