Although paracetamol (acetaminophen) is one of the most consumed over-the-counter analgesic and antipyretic agents, its mechanism of action is unclear. The metabolism and action of paracetamol is complex and possibly dependent on the dose and route of administration. We have found that the paracetamol metabolite p-aminophenol is metabolised by fatty acid amide hydrolase (FAAH) to the TRPV1 activator N-arachidonoylphenolamine (AM404) in the central nervous system. The antinociceptive effect of paracetamol is absent in FAAH and TRPV1 knockout mice and in wild type mice given the TRPV1 antagonist capsazepine intracerebroventricularly, suggesting that activation of TRPV1 on descending inhibitory neurons in the brain are involved in the antinociceptive effect. In another study we have shown that paracetamol via some of its electrophilic metabolites is antinociceptive via activation of TRPA1 in the mouse spinal cord. However, electrophilic compounds are tissue damaging and not suitable as drugs. It is therefore of interest that intrathecal administration of delta-9-tetrahydrocannabiorcol, a cannabinoid derivative without CB1/CB2 receptor agonistic properties, also produced spinal TRPA1-mediated antinociception. Our studies show that paracetamol is antinociceptive via activation of TRPV1 and TRPA1. We provide a conceptual framework for the use of 1) drug molecules that are converted to bioactive N-acylamines acting on TRPV1 and other molecular targets involved in noxious signalling in the central nervous system, and 2) non-electrophilic TRPA1 activators to achieve analgesia at the level of the spinal cord.