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Eur J Pharmacol. 2006 May 24;538(1-3):57-65. Epub 2006 Apr 1.

The involvement of a cyclooxygenase 1 gene-derived protein in the antinociceptive action of paracetamol in mice.

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The Experimental Pathology Group, the William Harvey Research Institute, the John Vane Science Centre, St. Bartholomew's and the London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom.


Paracetamol is a widely used analgesic and antipyretic with weak anti-inflammatory properties. Experimental evidence suggests that inhibition of prostaglandin biosynthesis contributes to its pharmacological actions. Three cyclooxygenase (COX) isoenzymes are involved in prostaglandin biosynthesis, COX-1, COX-2 and a recently discovered splice-variant of COX-1, COX-3. Our aim was to identify the relative roles for these enzymes in the antinociceptive action of paracetamol in mice. We compared the antinociceptive action of paracetamol with the non-selective non-steroid anti-inflammatory drug, diclofenac and studied paracetamol antinociception in COX-1 and COX-2 knockout mice. Paracetamol (100-400 mg/kg) inhibited both acetic acid- and iloprost-induced writhing responses. In contrast, diclofenac (10-100 mg/kg) inhibited only acetic acid-induced writhing. Only diclofenac reduced peripheral prostaglandin biosynthesis whereas both drugs reduced central prostaglandin production. Prostaglandin E(2) (PGE(2)) concentrations were reduced in different brain regions by administration of paracetamol. COX-1, COX-2 and COX-3 enzyme proteins were expressed in the same brain regions. The effects of paracetamol on writhing responses and on brain PGE(2) levels were reduced in COX-1, but not COX-2, knockout mice. The selective COX-3 inhibitors, aminopyrine and antipyrine also reduced writhing responses and brain PGE(2) biosynthesis. These results suggest that the antinociceptive action of paracetamol may be mediated by inhibition of COX-3.

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