**1. Introduction**

More than a century after its discovery, paracetamol (acetaminophen) is the most widely prescribed analgesic in the world. Although used as a treatment for moderate pain and fever for more than a century, the mechanisms of its analgesic action are poorly understood and are a topic of ongoing debate. This chapter presents and updates the preclinical data on the pharmacodynamics of the paracetamol. While the two main mechanisms are considered as based

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on the inhibition of cyclooxygenases and/or the activation of the serotonergic system [1], we show that the endocannabinoid and vanilloid systems and the T-type calcium-channel Cav3.2 are emerging as new targets of its action *via* complex metabolic and neuronal pathways.
