Involvement of 5-HT(1A/1B) receptors in the antinociceptive effect of paracetamol in the rat formalin test

The mechanism of analgesic action of paracetamol (acetominophen) remains still unknown. However, a relationship between serotonergic system and the effect of paracetamol has been previously demonstrated. The serotonin activity in the brainstem is primarily under the control of 5-HT(1A) somatodendritic receptors, although some data also suggest the involvement of 5-HT(1B) receptors. To determine whether the 5-HT(1A) and 5-HT(1B) receptors are involved in the antinociceptive effect of paracetamol, we evaluated the effect of paracetamol (0.125–1 g/kg i.p.) followed by different antagonists [WAY 100,635 (0.8 mg/kg s.c.) and SB 216,641 (0.8 mg/kg s.c.)] or agonists [8-OH-DPAT (0.125 mg/kg s.c.) and CP 93,129 (0.125 mg/kg s.c.)] of 5-HT(1A) and 5-HT(1B) receptors, respectively, in the rat model of formalin-induced pain. We demonstrated that paracetamol administration showed a dose-dependent antinociceptive effect in the formalin test. WAY 100,635 (5-HT(1A) antagonist) induced an increase in the antinociceptive effect of paracetamol at 250 mg/kg doses. Conversely, 8-OH-DPAT (5-HT(1A) agonist) decreased the antinociceptive effect of paracetamol at 500–1000 mg/kg doses. However, SB216641 (5-HT(1B) antagonist) modified weakly the antinociceptive effect of paracetamol at 250 mg/kg doses and CP 93,129 (5-HT(1B) agonist) not produce a clear effect in the antinociceptive effect of paracetamol. These results suggest that the antinociceptive effect of paracetamol can be enhanced mainly by compounds having 5-HT(1A) antagonist properties in the formalin test and maybe by 5-HT(1B) receptors antagonists.