Evaluation of the Centrally-Acting Mechanisms of Some Non-Steroidal Anti-inflammatory Drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) whose main mechanism is inhibition of cyclooxygenases are commonly used for the management of pain. However, this mechanism is inadequate to explain the central analgesic activity of these drugs. We aimed to examine and to compare the central analgesic activity of diclofenac, etodolac, and indomethacin and the possible involvement of serotonergic and adrenergic mechanisms in their effects by using the hot plate and tail immersion tests. All drugs were assessed at same single doses (10 mg/kg). Mice were pretreated with prazosin and yohimbine, adrenergic antagonists, (1 mg/kg; i.p., 30 min. before testing) for investigating adrenergic mechanisms. Ondansetron and ketanserin, serotonergic antagonists, (0.5 mg/kg; i.p., 30 min. before testing) were also used for investigating serotonergic mechanisms. In tail immersion test, yohimbine and ketanserin decreased the antinociceptive effects of all tested NSAIDs. Ondansetron only antagonized the antinociceptive effect of diclofenac while prazosin was found ineffective. In the hot plate test, prazosin attenuated the antinociceptive effect of indomethacin and etodolac. Yohimbine, ondansetron, and ketanserin reversed the antinociceptive effects of all test drugs. The antinociception induced by tested drugs appears to be mediated either serotonergic (5-HT2/5-HT3) or adrenergic (α1/α2) receptors in spinal/supraspinal level. 5-HT2/ 5-HT3 and α1/α2 receptors are more associated with the supraspinal antinociceptive effect of NSAIDs while 5–HT2 and α2 receptors are predominantly involved in antinociceptive effect at the spinal level.