The paracetamol metabolite NAPQI reduces excitability in first and second order neurons of the pain pathway through actions on K v 7 channels

Paracetamol (acetaminophen, APAP) is one of the most frequently used analgesic agents worldwide. It is generally preferred over non-steroidal antiinflammatory drugs (NSAIDs) as it does not cause typical adverse effects resulting from the inhibition of cyclooxygenases, such as gastric ulcers. Nevertheless, inhibitory impact on these enzymes is claimed to contribute to paracetamols mechanisms of action which, therefore, remained controversial. Recently, the APAP metabolites N-arachidonoylaminophenol (AM404) and N-acetyl-p-benzoquinone imine (NAPQI) have been detected in the central nervous system after systemic APAP administration and were reported to mediate paracetamol effects. In contrast to NSAIDs which rather support seizure activity, paracetamol provides anticonvulsant actions, and this dampening of neuronal activity may also form the basis for analgesic effects. Here we reveal that the APAP metabolite NAPQI, but neither the parent compound nor the metabolite AM404, reduces membrane excitability in rat dorsal root ganglion (DRG) and spinal dorsal horn (SDH) neurons. The observed reduction of spike frequencies is accompanied by hyperpolarization in both sets of neurons. In parallel, NAPQI, but neither APAP nor AM404, increases currents through Kv7 channels in DRG and SDH neurons, and the impact on neuronal excitability is absent if Kv7 channels are blocked. Furthermore, NAPQI can revert the inhibitory action of the inflammatory mediator bradykinin on Kv7 channels, but does not affect synaptic transmission between DRG and SDH neurons. These results show that the paracetamol metabolite NAPQI dampens excitability of first and second order neurons of the pain pathway through an action on Kv7 channels. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Correspondence to: Stefan Boehm, Division of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Waehringer Strasse 13a, 1090 Vienna, Austria, Phone: +43 1 40160 31200; Fax: +43 1 40160 931201, stefan.boehm@meduniwien.ac.at. Europe PMC Funders Group Author Manuscript Pain. Author manuscript; available in PMC 2019 April 01. Published in final edited form as: Pain. 2019 April ; 160(4): 954–964. doi:10.1097/j.pain.0000000000001474. E uope PM C Fuders A uhor M ancripts E uope PM C Fuders A uhor M ancripts