Mechanism of the antinociceptive effect of paracetamol

The mechanism of action of paracetamol (acetaminophen) is still not clearly understood. Unlike morphine, for example, paracetamol has no known endogenous high-affinity binding sites. In addition, paracetamol does not appear to share with nonsteroidal anti-inflammatory drugs (NSAIDs) the capacity to inhibit peripheral cyclo-oxygenase (COX) activity. There is currently considerable evidence to support the hypothesis of a central antinociceptive effect. Although various biochemical studies point to inhibition of central COX-2 activity, the existence of a COX activity that is selectively susceptible to paracetamol (COX-3?) is an alternative hypothesis. Modulation of the serotoninergic system has also been suggested on the basis of biochemical and behavioural studies supporting an indirect serotoninergic (5-HT) effect. Paracetamol may stimulate the activity of descending 5-HT pathways that inhibit nociceptive signal transmission in the spinal cord. Support for this possibility has come from evidence that spinally administered antagonists of several 5-HT receptor subtypes abolish the antinociceptive activity of paracetamol. These hypotheses have yet to be confirmed by further studies. Until then, the primary pharmacological mechanism underlying the analgesic effect of paracetamol has still to be clearly defined.