Researchers at the Hebrew University of Jerusalem have discovered a new mechanism showing that paracetamol, also known as acetaminophen, alleviates pain by acting outside the brain. Published in the June 2025 issue of the Proceedings of the National Academy of Sciences USA (PNAS), the study reveals that paracetamol’s active metabolite, AM404, targets specific sodium channels in pain-sensing neurons. This process halts pain signals before they reach the brain and challenges the long-held belief that paracetamol works solely within the brain and spinal cord.
For years, scientists believed that the drug’s pain-relieving effects were limited to the central nervous system. However, the study now shows that AM404, which forms in the body after paracetamol is ingested, acts directly on peripheral nerves where pain is initially detected. By blocking sodium channels responsible for transmitting pain, AM404 prevents the signal from reaching the central nervous system.
“This is the first time we have shown that AM404 works directly on the nerves outside the brain,” said Professor Alexander Binshtok from the Hebrew University’s Faculty of Medicine and the Edmond and Lily Safra Center for Brain Sciences. “It changes our entire understanding of how paracetamol fights pain.”
The research was led by Professor Binshtok and Professor Avi Priel from the School of Pharmacy. Prof. Priel said, “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.” He explained that unlike traditional local anaesthetics, which often cause numbness or muscle weakness, AM404 acts specifically on pain-carrying nerves, which could reduce such side effects and improve patient comfort.
The study, titled “The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels,” was conducted by a team that included Yossef Maatuf, Yishai Kushnir, Alina Nemirovski, Mariana Ghantous, and Ariel Iskimov. They represented the Institute for Drug Research, the School of Pharmacy, the Department of Medical Neurobiology, and the Mass Spectrometry Unit at the Hebrew University.
The research highlights a significant shift in how pain relief could be approached. Current painkillers such as local anaesthetics often affect a wide range of nerve functions, sometimes leading to unwanted effects. The discovery that AM404 can block only the relevant sodium channels offers hope for new treatments that relieve pain without interfering with other sensory or motor functions.
As the Hebrew University marks its centennial in 2025, this discovery adds to its legacy of innovation. With more than 23,000 students from 80 countries, the university contributes nearly 40% of Israel’s civilian scientific research and holds over 11,000 patents. Its academic community includes nine Nobel Prize winners and a Fields Medal recipient. Support from the American Friends of the Hebrew University, a non-profit based in the United States, continues to fund scholarships, faculty recruitment, and the development of new research facilities.
The study aligns with a growing interest in improving how pain is managed around the world. As millions of people live with chronic pain, the potential for AM404-based treatments offers a new direction for more precise and effective therapies. The peer-reviewed findings in PNAS lay the groundwork for future clinical trials and the development of next-generation painkillers.
