How Acetaminophen (Tylenol) Works

Today while administering acetaminophen to my two year old boy I wondered what was the state of our knowledge of how it worked. I found this new paper “TRPV-1 in Brain Is Involved in Acetaminophen-Induced Antinociception” published September 17, 2010 in PLoS ONE.

Mechanism behind the TRPV-1 mediated anti-pain effect of acetaminophen.
Figure 1. A diagram showing the TRPV-1 mediated mechanism proposed to lead to the pain reducing effect of acetaminophen. Please see text below for details. From “TRPV-1 in Brain Is Involved in Acetaminophen-Induced Antinociception“. By Christophe Mallet, David A. Barrière, Anna Ermund, Bo A. G. Jönsson, Alain Eschalier, Peter M. Zygmunt, and Edward D. Högestätt. PLoS ONE Volume 5, Number 9, September 17, 2010.

Through a set of experiments on mice and rats the authors provide evidence that the capsaicin receptor (TRPV1; see note below) mediates the pain reducing effect of acetaminophen. That might sound odd to you since the capsaicin receptor is best know as causing painful, burning sensations when activated. Very spicy food activates capsaicin receptors as does touching something hot. These examples activate capsaicin receptors in the peripheral nervous system. In contrast, the capsaicin receptors that appear to mediate the pain reducing effect of acetaminophen are located in the central nervous system. The authors suggest that activation of capsaicin receptors in the central nervous system could produce its effects by stimulating bulbospinal descending inhibitory pathways in the periaqueductal gray.

Note: Capsaicin receptors are currently referenced more technically as the transient receptor potential cation channel, subfamily V, member 1 (TRPV1). The protein is encoded by the TRPV1 gene.

Based on their findings, the authors propose the following mechanism behind the pain reducing effect of acetaminophen (see Figure 1 above). The liver metabolizes acetaminophen (AcAP) to p-aminophenol (p-AP). Fatty acid amide hydrolase (FAAH) containing neurons in the central nervous system conjugate p-AP with arachidonic acid (AA), which leads to the formation of the capsaicin receptor (TRPV1) activator AM404. The authors suggest that AM404 may activate capsaicin receptors from inside the neuron.

As the authors point out, there is no consensus on how acetaminophen works. The paper under review provides intriguing glimpses at what might be happening when we ingest acetaminophen. Also, their data indicate that acetaminophen and ibuprofen provide pain relief through different mechanisms.

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