June 9, 2025 – Hebrew University of Jerusalem (HU) researchers have discovered a new mechanism that shows how paracetamol (acetaminophen) works outside the brain—a mechanism that may lead to safer, more targeted pain treatments. Published in the Proceedings of the National Academy of Sciences USA (PNAS), the researchers found that the active metabolite in paracetamol, AM404, shuts down specific sodium channels in pain-sensing neurons, stopping pain signals before they reach the brain. This discovery reshapes the understanding of how one of the world’s most common painkillers works. For decades, scientists believed that paracetamol relieved pain by working only in the brain and spinal cord. This study shows that the drug also works outside the brain, in the nerves that first detect pain.

Upon ingesting paracetamol, AM404 is produced in the pain-sensing nerve endings, and shuts off specific channels that help transmit pain signals. By blocking these channels, AM404 stops the pain message before it even starts.

This breakthrough could also lead to new types of painkillers. Because AM404 targets only the nerves that carry pain, it may avoid the numbness, muscle weakness, and side effects that accompany traditional local anesthetics.

The study was led by Prof. Alexander Binshtok from the Hebrew University’s Faculty of Medicine and the Edmond & Lily Safra Center for Brain Sciences (ELSC) and Prof. Avi Priel from HU’s School of Pharmacy. “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 paracetamol fights pain.”

“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.

The study, “The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels,” appears in the June 2025 issue of PNAS, a leading journal of the U.S. National Academy of Sciences, and can be accessed here.

Researchers:

Yossef Maatuf1, Yishai Kushnir2,3, Alina Nemirovski4, Mariana Ghantous1, Ariel Iskimov1, Alexander M. Binshtok2,3, Avi Priel1

Institutions:

1. The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem
2. Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem
3. The Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem
4. Mass Spectrometry Unit, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem