Opioid system mediated anti-nociceptive effect of agomelatine in mice

Abstract

Aims: This study was planned to examine the antinociceptive efficacy of agomelatine against acute mechanical, thermal, and chemical nociceptive stimuli, as well as to determine the opioid receptor subtypes mediating these effects. Main methods: Tail-clip, hot-plate, and acetic acid-induced writhing tests were performed to evaluate antinociceptive effect. Besides, possible effect of agomelatine on the motor coordination of animals was assessed with a Rota-rod test. Keyfindings: Agomelatine (40 mg/kg and 60 mg/kg) significantly prolonged the reaction time of mice in both the tail-clip and hot-plate tests, suggesting the antinociceptive activity is related to both spinal and supraspinal mechanisms. This drug also reduced the number of writhing behaviors indicating the presence of a peripherally mediated antinociceptive effect Rota-rod testing displayed no notable effect on the motor activity of the animal supporting the conclusion that the observed antinociceptive effect is specific. The agomelatine-induced antinociceptive activity abrogated following pretreatment with naloxone (a non-selective opioid receptor antagonist, 5.48 mg/kg, i.p.), which suggested the participation of opioid mechanisms to the antinociception. The possible contribution of mu, delta and kappa subtypes of opioid receptors to the anti-nociceptive effect were evaluated using naloxonazine (7 mg/kg, s.c.), naltrindole (0.99 mg/kg, i.p.), and nor-binaltorphimine (1.03 mg/kg, i.p.), respectively. Pretreatments using these antagonists abolished the antinociceptive activity of agomelatine in all of the nociceptive test paradigms used, which pointed out that mu, delta, and kappa opioid receptors participated to the action of agomelatine on pain. Significance: These results demonstrated the therapeutic potential of agomelatine in the treatment of pain disorders