A groundbreaking study from the Hebrew University of Jerusalem, recently published in the prestigious journal PNAS (Proceedings of the National Academy of Sciences USA), has unveiled a fresh perspective on how paracetamol (also known as acetaminophen, Tylenol®, or Panadol®) alleviates pain.
The research, led by Prof. Alexander Binshtok from the Faculty of Medicine and the Center for Brain Sciences (ELSC) and Prof. Avi Priel from the School of Pharmacy, challenges decades of understanding regarding the mechanism of this widely-used painkiller.
For many years, scientists believed that the analgesic properties of paracetamol were limited to its action in the brain and spinal cord. However, the new findings indicate that the drug also exerts its effects in the peripheral nerves responsible for detecting pain.
The team made a significant discovery centered around a compound known as AM404, which is synthesized in the body after the ingestion of paracetamol.
Through rigorous experimentation, the researchers observed that AM404 is generated directly within the pain-sensing nerve endings. This compound plays a crucial role by blocking sodium channels that are involved in transmitting pain signals.
In doing so, AM404 effectively halts the pain message before it can reach the brain, marking a profound shift in our understanding of paracetamol’s role in pain management.
“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.”
This revelation not only alters the scientific narrative surrounding paracetamol but could also lay the groundwork for developing new, more effective pain relief options.
Because AM404 specifically targets the pain-transmitting nerves, it holds the potential to avoid the complications often associated with traditional local anesthetics, such as numbness and muscle weakness.
“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, emphasizing the therapeutic potential of this finding.
The study published by Binshtok and Priel highlights that paracetamol has long been a staple in relieving mild-to-moderate pain, primarily attributed to its metabolite AM404 and its interactions with cannabinoid receptors or TRPV1 channels in the central nervous system (CNS).
However, the latest findings illustrate that AM404 is produced by primary sensory neurons and directly inhibits sodium currents in nociceptor neurons by obstructing action potential (AP) generation.
This inhibition reduces nocifensive behavior in both naïve and inflamed rats, indicating a direct analgesic effect that is exclusive to AM404 and not seen with other paracetamol metabolites.
The researchers demonstrated that AM404 specifically inhibits nociceptive voltage-gated sodium channels (NaV) 1.8 and 1.7 at the local anesthetic binding site, paving the way for future studies aimed at further investigating this novel mechanism of action.
As such, the implications of this research could guide the development of AM404 as a highly selective local analgesic, subsequently advancing the field of pain management.
In summary, the discovery that paracetamol acts on peripheral pain-sensing nerves opens new avenues for safer, more effective pain relief strategies, shifting the paradigm of how we understand this common drug’s action in the body.
This study not only enhances our comprehension of existing medications but may also lead to innovative therapies that could drastically improve the quality of pain management for individuals in need.
image source from：https://neurosciencenews.com/acetaminophen-pain-neurology-29243/
