Scientists have discovered that acetaminophen doesn’t only work in the brain, it also blocks pain directly in nerve endings.
Researchers at the Hebrew University of Jerusalem have found that acetaminophen doesn’t only act in the brain. Their study reveals that it also blocks pain at its origin by targeting nerve endings in the body. The team discovered that its active compound, AM404, interferes with sodium channels in pain-sensing neurons, stopping pain signals before they reach the brain.
This discovery transforms scientists’ understanding of one of the world’s most widely used painkillers. By showing that acetaminophen works both in the nervous system and at the site of pain, the findings could guide the creation of next-generation pain treatments designed to be more effective and gentler on the body.
Published in the Proceedings of the National Academy of Sciences, the study was conducted by Prof. Alexander Binshtok from the Faculty of Medicine and Center for Brain Sciences (ELSC) and Prof. Avi Priel from the School of Pharmacy at Hebrew University. Together, their research uncovered a previously unknown mechanism of pain relief, challenging long-standing assumptions about how acetaminophen functions in the body.
Acetaminophen (also called paracetamol, Tylenol, or Panadol) is one of the most commonly used pain and fever medications worldwide. It is known for effectively easing mild to moderate pain and reducing fever, without the stomach irritation or anti-inflammatory effects often linked to drugs like aspirin or ibuprofen.
Beyond the Brain: A Peripheral Pathway
For decades, scientists believed that acetaminophen relieved pain by working only in the brain and spinal cord. But this new research, published in PNAS, shows that the drug also works outside the brain, in the nerves that first detect pain.
Their discovery centers on a substance called AM404, which the body makes after taking acetaminophen. The team found that AM404 is produced right in the pain-sensing nerve endings—and that it works by shutting off specific channels (called sodium channels) that help transmit pain signals. By blocking these channels, AM404 stops the pain message before it even starts.
“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.”
Toward Safer, Smarter Pain Treatments
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 come with traditional 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.
Reference: “The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels” by Yossef Maatuf, Yishai Kushnir, Alina Nemirovski, Mariana Ghantous, Ariel Iskimov, Alexander M. Binshtok and Avi Priel, 4 June 2025, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2413811122
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