ELSC Seminar Series

Abstract: Paracetamol is the most commonly used analgesic worldwide. However, how exactly paracetamol alleviates pain remains unclear. We discovered that paracetamol produces analgesia peripherally via its bioactive metabolite AM404. We show that AM404 inhibits sodium current selectively in peripheral nociceptor neurons to block action potential generation and reduce nocifensive behavior in naïve and inflamed rats. We demonstrated that this analgesic effect of AM404 is mediated by its direct inhibition of nociceptive voltage-gated sodium channels (NaV)1.8 and 1.7 via the local anesthetic binding site. The NaV1.8 and 1.7 inhibition was specific for AM404 and not observed with other metabolites of paracetamol. Our findings provide the first evidence that paracetamol confers its analgesic effect via direct and selective AM404-mediated inhibition of nociceptive sodium channels at the peripheral nociceptor neurons.