Acetaminophen exerts its pain-relieving effects with help from a cation channel protein called TRPA1, according to studies conducted in rodents (Nat. Commun., DOI: 10.1038/ncomms1559). The discovery suggests that TRPA1 could be a viable target for new pain relievers. Also known as paracetamol, acetaminophen is one of the most widely used analgesics. But how it works is still unclear. Among the drug’s proposed targets are cyclooxygenases, which are enzymes with connections to pain pathways. Edward D. Högestätt of Sweden’s Lund University, Stuart Bevan of King’s College London, and coworkers report that mice lacking TRPA1, a sensor for irritants such as compounds in horseradish, don’t experience pain relief after receiving acetaminophen. In the team’s ion-channel studies, certain reactive acetaminophen metabolites, including N-acetyl-p-benzoquinonimine, activated TRPA1 and reduced calcium and sodium currents in sensory neurons. The team detected both TRPA1 and a stable derivative of N-acetyl-p-benzoquinonimine in rodent spinal cord samples, which they say suggests that the spinal cord is the site of TRPA1 activation.