By Morgan Nwanguma
Acetaminophen may be doing more than just easing pain in the brain — it could be stopping it at the source. New research from the Hebrew University of Jerusalem reveals that a key metabolite of the drug, known as AM404, blocks pain signals at their origin by shutting down specific sodium channels in pain-sensing nerves. This surprising discovery challenges long-held assumptions about how acetaminophen works and suggests it acts not only in the brain but also directly on nerve endings in the body. The findings could pave the way for a new generation of targeted painkillers that are more effective and come with fewer side effects, such as numbness or muscle weakness.
Thus scientists have discovered a surprising new dimension to acetaminophen: it not only dulls pain in the brain but also targets pain at its source in the body. The study reveals that the drug’s active metabolite, AM404, blocks specific sodium channels in pain-sensing neurons, effectively halting pain signals before they even reach the brain. This breakthrough challenges long-standing beliefs about how acetaminophen works and could revolutionize the way we approach pain relief — leading to more precise treatments with fewer side effects.
The groundbreaking study, published recently in the prestigious journal PNAS (Proceedings of the National Academy of Sciences USA), has revealed a previously unknown mechanism through which acetaminophen — also known as paracetamol, Tylenol®, or Panadol® — relieves pain.
Led by Prof. Alexander Binshtok of the Faculty of Medicine and the Edmond & Lily Safra Center for Brain Sciences (ELSC), along with Prof. Avi Priel from the School of Pharmacy, the research uncovers a surprising new way this widely used painkiller actually works.
For decades, scientists believed acetaminophen acted solely within the brain and spinal cord. But this new research shows it also operates in the peripheral nervous system — specifically in the pain-detecting nerves themselves.
The key lies in a compound called AM404, a metabolite produced in the body after acetaminophen is taken. The researchers found that AM404 forms directly in pain-sensing nerve endings and works by shutting down certain sodium channels critical for transmitting pain signals. By blocking these channels, AM404 prevents pain from traveling to the brain in the first place — offering a new perspective on how pain can be managed more effectively.
“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.”
This breakthrough could pave the way for a new class of painkillers. Since AM404 specifically targets pain-transmitting nerves, it may offer relief without the numbness, muscle weakness, or other side effects often associated 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.
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