Mechanisms involved in the antinociception caused by melatonin in mice

<jats:p><jats:bold>Abstract: </jats:bold>The present study assesses the antinociceptive effect of melatonin in chemical behavioral models of nociception and investigates some of the mechanisms underlying this effect. Melatonin administered by intraperitoneal (i.p., 10–100 mg/kg), intracerebroventricular (i.c.v., 250–500 pmol/site) and intraplantar (i.pl., 30–100 ng/i.pl.) routes, reduced in a dose‐dependent manner the nociception caused by i.pl. injection of glutamate (10 <jats:italic>μ</jats:italic>mol/paw), with mean ID<jats:sub>50</jats:sub>values of 32.6 mg/kg, 200 pmol/site and 59 ng/i.pl., respectively. Furthermore, melatonin in the dose range of 10–100 mg/kg, i.p., reduced the neurogenic pain caused by i.pl. injection of capsaicin (5.2 nmol/paw) with inhibition of 48 ± 4%. The antinociceptive effect of melatonin (100 mg/kg, i.p.) on glutamate‐induced nociception was completely prevented by the pretreatment of animals with naloxone (a nonselective opioid receptor antagonist, 1 mg/kg, i.p.), ketanserin (a preferential 5‐HT<jats:sub>2<jats:italic>A</jats:italic></jats:sub>receptor antagonist, 1 mg/kg, i.p.), sulpiride (a D<jats:sub>2</jats:sub>receptor antagonist, 50 mg/kg, i.p.),<jats:sc>l</jats:sc>‐arginine (a precursor of nitric oxide, 600 mg/kg, i.p.), yohimbine (an<jats:italic>α</jats:italic><jats:sub>2</jats:sub>‐adrenoceptor antagonist, 0.15 mg/kg, i.p.) and luzindole (a preferential MT<jats:sub>2</jats:sub>receptor antagonist, 10 mg/kg, i.p.), but was not affected by the pretreatment with<jats:sc>d</jats:sc>‐arginine (an inactive isomer of<jats:sc>l</jats:sc>‐arginine, 600 mg/kg, i.p.), prazosin (an<jats:italic>α</jats:italic><jats:sub>1</jats:sub>‐adrenoceptor antagonist, 0.15 mg/kg, i.p.) or after bilateral adrenalectomy. Collectively, present results suggest that melatonin produces peripheral and central antinociception when assessed on capsaicin‐ or glutamate‐induced pain in mice through mechanisms that are likely mediated by interaction with plasma membrane‐bound melatonin receptors and modulated by opioid, serotonergic (5‐HT<jats:sub>2<jats:italic>A</jats:italic></jats:sub>receptors), dopaminergic (D<jats:sub>2</jats:sub>‐receptors), adrenergic (<jats:italic>α</jats:italic><jats:sub>2−</jats:sub>adrenoceptors) systems as well as the<jats:sc>l</jats:sc>‐arginine‐nitric oxide pathway.</jats:p>