Abstract
Paracetamol (acetaminophen, APAP) is one of the most frequently used analgesic agents worldwide. It is generally preferred over nonsteroidal anti-inflammatory drugs because 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 nonsteroidal anti-inflammatory drugs that 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.
Highlights
Paracetamol is often referred to as the drug that is used most frequently around the globe to treat mild to moderate pain and to reduce fever.[5,17] It is generally favored over nonsteroidal anti-inflammatory drugs (NSAIDs) as it provokes serious adverse events less frequently
The present results demonstrate that the paracetamol metabolite N-acetylp-benzoquinone imine (NAPQI) reduces excitability and causes membrane hyperpolarization in dorsal root ganglion (DRG) and spinal dorsal horn (SDH) neurons, first- and second-order nerve cells in the pain pathway
As neuronal TRP channels are permeable to, but rather nonselective for different cations, their activation results in depolarization rather than hyperpolarization.[50]. This mechanism explains why NAPQI led to a depolarizing response in DRG neurons, once KV7 channels were blocked by linopirdine (Fig. 4)
Summary
Paracetamol (acetaminophen) is often referred to as the drug that is used most frequently around the globe to treat mild to moderate pain and to reduce fever.[5,17] It is generally favored over nonsteroidal anti-inflammatory drugs (NSAIDs) as it provokes serious adverse events less frequently.
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