Effect of rofecoxib on nociception and the serotonin system in the rat brain

Abstract.

Objective and design: The purpose of the present study was to determine whether the antinociceptive activity of rofecoxib is mediated, at least in part, through changes in the brain serotonergic system.¶Materials and subjects: Male Wistar rats weighing 180-200 g (groups of eight) were subjected to the hot-plate and formalin tests after rofecoxib treatment. Cortical areas were removed for serotonin (5-HT) level, 5-HT₂ and μ-receptor evaluation.¶Treatment: Rofecoxib was administered orally at doses of 5, 10, 20 and 50 mg/kg for the time course evaluation in the hot-plate test (30, 60 and 120 min), and at the dose of 10 mg/kg for the formalin test and biochemical determinations.¶Methods: The tests performed were the hot-plate and the formalin assays. HPLC was used to determine 5-HT levels and radioligand-binding assays were utilized to evaluate the characteristics of 5-HT₂ and μ-receptors. The data were analysed by ANOVA or Student's t test.¶Results: The lowest active dose of rofecoxib in the hot-plate test was 10 mg/kg. The percentage of the maximum possible effect (%MPE) values were: control = 1.7 ± 3.4; treated 23.4 ± 6.5 (p<0.05). The same dose had a significant effect on both phases of the formalin test. Pretreatment with p-chlorophenylalanine (PCPA) significantly decreased the activity of rofecoxib in the hot-plate test. Rofecoxib treatment increased serotonin levels and decreased the maximum number of 5-HT₂ receptors. 5-HT levels (ng/g) were: control = 240.1 ± 28.5, rofecoxib = 326.1 ± 19.9 in the frontal cortex. The characteristics of μ-receptors did not change.¶Conclusions: These results suggest that rofecoxib may exert its therapeutic effect, at least in part, through the central serotonergic system. The opioidergic system, on the other hand, seems to be unaffected.