How does paracetamol work?

Question

[Hinz *et al.* 2008](https://www.ncbi.nlm.nih.gov/pubmed/17884974) found that COX-2 may be inhibited by paracetamol, and this is attributed to it's [analgesic](https://en.wikipedia.org/wiki/Analgesic) and [antipyretic](https://en.wikipedia.org/wiki/Antipyretic) properties. However there are other more recent claims from [Andersson *et al.,* 2011](http://www.nature.com/ncomms/journal/v2/n11/full/ncomms1559.html) that a toxic intermediate metabolite, NAPQI, may be acting on TRPA1-receptors in the spinal chord. Whilst I'm vaguely aware that the end goal is to affect prostaglandins, to me at least it remains unclear how that translates to painkilling.There are also other theories I would imagine.This excedingly common drug seems shrouded in mystery. I know very little about pharmacology (*evidently!*), so some expert insight into the popular theories, and *why* they're popular, would be greatly appreciated. - What are the most popular theories in a nutshell? - *Why are they a popular theory?* - *Which protein is targeted?* - *How does that inhibition introduce the analgesic and antipyretic properties?* - Is it possible multiple theories are correct? - *(on the side)* Why is so little known about paracetamol? Is it exceptionally difficult, or the norm in pharmaceutical research of relatively old effective drugs? *If it ain't broken, why fix it!*

Answer 1

Paracetamol is the same as acetaminophen. Most popular brand name is Tylenol in the U.S. In Europe its known as paracetamol. The exact mechanism of action is not fully understood. It may be due to activation of CNS inhibitory serotonergic pathways, modulation of nociceptive systems, and/or modulation of endogenous CNS cannabinoid system. COX reduction occurs only within the CNS to reduce pain and fever, and therein lies its distinction from NSAID's.