Evaluating the antinociceptive effects of agomelatine with experimental acute nociceptive models

Agomelatine is a new antidepressant drug, acts through a unique mechanism of action, as a MT1 and MT2 melatonergic receptor agonist and a 5-HT2C serotonergic receptor antagonist. This thesis study was planned to investigate antinociceptive effect of agomelatine against acute mechanical, thermal and chemical nociceptive stimulus as well as to determine the opioid receptor subtypes mediating these effects. Hot plate, tail-clip and acetic acid induced writhing tests were performed with this purpose. Agomelatine (40 mg.kg-1 and 60 mg.kg-1) significantly increased the reaction time of mice both in the hot-plate and the tail-clip tests, suggesting the supraspinally and spinally mediated antinociceptive effect of this drug. Agomelatine administration also reduced the number of acetic acid induced writhing behaviours indicating the presence of peripherally mediated antinociceptive effect, as well as centrally mediated ones. On the other hand, falling latencies of mice in the Rota-rod test did not change upon the administration of agomelatine, which indicated that this drug showed specific anti-nociceptive effect. Agomelatine induced antinociceptive effect disappeared by pre-treatment with non-selective opioid receptor antagonist naloxone (5.48 mg/kg, i.p), which indicated the involvement of opioid mechanisms in the observed antinociception. Possible contribution of µ, δ and ҡ subtypes of opioid receptors to the antinociceptive activity were evaluated by using naloxonazine (7 mg/kg, s.c), naltrindole (0.99 mg/kg, i.p), and nor-binaltorphimine (1.03 mg/kg, i.p), respectively. Pretreatment using naloxonazine, naltrindole, and nor-binaltorphimine reversed the antinociceptive effect of agomelatine in all of the nociceptive tests, which indicated that μ, δ and ҡ opioid receptors contributed to the antinociceptive effect of this drug. This thesis study is the first research exhibiting μ, δ and ҡ opioid receptor mediated acute antinociceptive effect of agomelatine.