Effects of acetaminophen on neuronal activity in the mouse locus coeruleus

Acetaminophen is widely used for the treatment of fever and pain. Although the analgesic effect of acetaminophen had been previously thought to be due to its anti–inflam­matory action by inhibiting prostaglandin production based on cyclooxygenase inhibition, it is currently considered that acetaminophen exerts its analgesic effects through the central actions of AM404, a metabolite of acetaminophen. However, the central mechanism is not yet fully understood. In the present study, we focused on the locus coeruleus (LC), which contains the largest population of noradrenergic neurons and is known as one of the descending pain modulatory systems, and investigated whether local administration of AM404 into the LC, or systemic application of acetamino­phen altered LC neuronal firing using an in vivo mouse extracellular rescoring technique. As results, we found that local LC administration of AM404, but not acetamino­phen, increased the firing frequency of LC neurons. Systemic acetaminophen application had also a similar excitatory action on LC neuronal activity. These results suggest that AM404, a metabolite of acetaminophen, acts centrally on the LC to increase its neuronal firing frequency. This central action may be one of the mechanisms for analgesic action of acetaminophen.