Involvement of serotonin mechanisms in the antinociceptive effect of S(+)-ketoprofen

Serotonin (5-hydroxytryptamine; 5-HT) plays a role in the modulation and processing of pain and evidence has been provided that some nonsteroidal anti-inflammatory drugs (NSAIDs) act, at least in part, through this system. The present study was designed to investigate the possible participation of 5-HT₁, 5-HT₂, 5-HT₃, and 5-HT₇ receptor subtypes in the antinociceptive effect of S(+)-ketoprofen (S-KP) at spinal and supraspinal level using the "pain induced functional impairment model in rat" (PIFIR model). S-KP was administered orally (p.o.) and antagonist drugs for 5-HT receptors (5-HT₁/5-HT₂, and 5-HT₃) were administered intrathecally (i.t.) or intracerebroventricularly (i.c.v.) 15 min before S-KP. S-KP (3.4 mg/kg p.o.) produced a significant antinociceptive effect in this model. Pre-treatment with the 5-HT₁/5-HT₂/5-HT₇ receptor antagonist, methiothepin (1.5 μg, i.c.v.), significantly reversed the antinociceptive effect of S-KP. In contrast, no significant differences were observed following i.t. administration of methiothepin. Pre-treatment i.t., but not i.c.v., with the 5-HT₃/5-HT₄ receptor antagonist, tropisetron (0.9 μg), on the other hand, significantly reversed S-KP-induced antinociception. These results indicate that serotonin mechanisms are involved in the antinociceptive effect of S-KP. 5-HT₁/5-HT₂/5-HT₇ receptors participate at the supraspinal level and 5-HT₃/5-HT₄ receptors participate at spinal level.