A groundbreaking study from the Hebrew University of Jerusalem has shed new light on how acetaminophen (paracetamol, Tylenol®, or Panadol®) alleviates pain. The research,published in PNAS (Proceedings of the National Academy of Sciences USA),details a previously unknown mechanism outside of the brain.

The study, spearheaded by Prof. alexander Binshtok from the Hebrew University’s Faculty of Medicine and Center for Brain Sciences (ELSC) and Prof.Avi Priel from its School of Pharmacy, reveals a surprising new action for one of the world’s most widely used painkillers.

For decades, the prevailing scientific understanding was that acetaminophen worked solely within the brain and spinal cord to reduce pain. However, this new research demonstrates that the drug also acts peripherally, directly on the nerves responsible for detecting pain.

The key to this discovery lies in a substance called AM404, a metabolite produced by the body after acetaminophen ingestion. The research team found that AM404 is generated within pain-sensing nerve endings, where it inhibits specific sodium channels crucial for transmitting pain signals. By blocking these channels, AM404 effectively halts the pain message at its origin.

“This is the first time we’ve shown that AM404 works directly on the nerves outside the brain,” said Prof. Binshtok.”It changes our entire understanding of how acetaminophen fights pain.”

Implications for Future Pain Relief

“If we can develop new drugs based on AM404, we might finally have pain treatments that are highly effective but also safer and more precise,”

This discovery could pave the way for the progress of novel pain medications. Because AM404 selectively targets pain-carrying nerves, it has the potential to avoid the numbness, muscle weakness, and other adverse effects associated with conventional local anesthetics.

“If we can develop new drugs based on AM404, we might finally have pain treatments that are highly effective but also safer and more precise,” added Prof.Priel.