Israeli scientists have uncovered a surprising mechanism behind paracetamol’s pain-relieving powers, with the potential to reshape how pain is treated, according to the Press Service of Israel (TPS-IL).

For years, researchers assumed that paracetamol—also known as acetaminophen, Tylenol, or Panadol — worked solely in the brain and spinal cord. But a new study, published in the peer-reviewed journal, PNAS, reveals that it also acts directly on the body’s peripheral nervous system.

Hebrew University researchers, led by Prof. Alexander Binshtok of the Faculty of Medicine and Center for Brain Sciences, and Prof. Avi Priel of the School of Pharmacy, discovered that a compound formed after taking paracetamol blocks specific sodium channels in pain-sensing neurons located throughout the body. These channels are responsible for transmitting pain signals from injured tissues to the brain.

The compound, called AM404, acts on different parts of the nervous system.

AM404 blocks specific voltage-gated sodium channels in peripheral nerves that are essential for transmitting pain signals to the brain. By inhibiting them, AM404 stops the pain message before it travels to the brain. AM404 also interacts with TRPV1 receptors which are involved in sensing heat and pain. Modulating these receptors can contribute to reducing pain sensations.

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

According to the study, AM404 targets only the neurons involved in pain signaling, essentially silencing them before the message of pain reaches the central nervous system.

“This explains why paracetamol is so effective, even though it lacks the numbing effects of anesthetics or the addictive potential of opioids,” Priel said. “We now understand that it blocks pain at the very first stage—right where it begins.”

This revelation has major implications for future pain treatment. Unlike local anesthetics, which can cause muscle weakness and numbness, AM404 appears to work selectively on pain pathways. That opens the possibility for developing next-generation drugs that are safer, more precise, and free of common side effects.

“If we can design new therapies based on AM404’s action, we might finally have effective painkillers that don’t impair movement or carry risks of addiction,” Priel said.