THE ANTINOCICEPTIVE ACTION OF PARACETAMOL IS ASSOCIATED WITH CHANGES IN THE SEROTONERGIC SYSTEM IN THE RAT-BRAIN

The antinociceptive activity of paracetamol in the hot plate and forma lin tests was studied to establish the relationship between antinocice ptive activity and the central serotonergic system. Significant antino ciceptive activity of paracetarnol was observed in the formalin test a t the dose of 300 mg/kg, while, at the dose of 400 mg/kg, the drug was active both in the formalin and in the hot-plate test. Serum paraceta mol levels remained sub-toxic and the behavioral profile remained unch anged. Depletion of brain serotonin with p-chlorophenylalanine prevent ed the antinociceptive effect of paracetamol in the hot-plate test and in the first phase of the formalin response. Paracetamol significantl y increased the serotonin content in the pontine and cortical areas (b y 75 and 70%, respectively). The pretreatment with p-chlorophenylalani ne reduced the 5-hydroxytryptamine (5-HT) content in cortical and pont ine areas to 12 and 19% of baseline values, respectively, and prevente d the enhancement induced by paracetamol. The maximum number of cortic al 5-HT2 receptors was reduced by paracetamol, while the number of 5-H T1A receptors in both cortical and pontine areas was unchanged. Pre-tr eatment with p-chlorophenylalanine prevented the reduction in the numb er of 5-HT2 receptors induced by paracetamol. These results provide ev idence for the involvement of the central serotonergic system in the a ntinociceptive effect of paracetamol in the hot plate and formalin tes ts.