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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 micromol/paw), with mean ID50 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-HT2A receptor antagonist, 1 mg/kg, i.p.), sulpiride (a D2 receptor antagonist, 50 mg/kg, i.p.), L-arginine (a precursor of nitric oxide, 600 mg/kg, i.p.), yohimbine (an alpha2-adrenoceptor antagonist, 0.15 mg/kg, i.p.) and luzindole (a preferential MT2 receptor antagonist, 10 mg/kg, i.p.), but was not affected by the pretreatment with D-arginine (an inactive isomer of L-arginine, 600 mg/kg, i.p.), prazosin (an alpha1-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-HT2A receptors), dopaminergic (D2-receptors), adrenergic (alpha2-adrenoceptors) systems as well as the L-arginine-nitric oxide pathway.

High-frequency stimulation (HFS) in human neocortical slices induces gamma-aminobutyric acid (GABA) release via GABA(A) receptor (GABA(A)R) activation. The mechanism of this effect and the localization of these GABA(A)Rs were now studied. Fresh human neocortical slices were subjected to HFS (130 Hz) in the presence of veratridine (3 microM). As measured by high-performance liquid chromatography, only GABA but not glutamate outflow was affected by HFS/veratridine stimulation. The evoked GABA overflow was abolished by tetrodotoxin and furosemide, suggesting an involvement of action potentials and plasmalemmal chloride gradients. Double immunolabeling showed that GABA(A)Rs are localized on soma and dendrites of GABAergic neurons in the human neocortex. Moreover, in support of a terminal localization of GABA(A)Rs, the K+-evoked [3H]-GABA release from synaptosomes was enhanced by the GABA(A)R agonist muscimol (antagonized by GABA(A)R blockers). We conclude that HFS in human brain neocortex leads to a specific increase of GABA release, which is mediated by facilitatory GABA(A) autoreceptors located on soma, dendrites, and axon terminals of GABAergic neurons.

Melatonin was previously shown to produce an antidepressant-like effect in the tail suspension test. In this work the mechanisms underlying its antidepressant-like effect were further studied by investigating the involvement of the dopaminergic system in its antidepressant-like effect in the tail suspension test. The effect of melatonin (1mg/kg, i.p.) was prevented by the pretreatment of mice with haloperidol (0.2mg/kg, i.p., a nonselective dopaminergic receptor antagonist), SCH23390 (0.05 mg/kg, s.c., a selective dopamine D1 receptor antagonist), and sulpiride (50mg/kg, i.p., a selective dopamine D2 receptor antagonist). The i.p. administration of melatonin (0.01 mg/kg) or fluoxetine (1mg/kg, a serotonin reuptake inhibitor) in combination with SFK38393 (0.1mg/kg, s.c., a dopamine D1 receptor agonist) reduced the immobility time in the tail suspension test as compared with either drug alone. Moreover, the pretreatment with melatonin (0.01 mg/kg, i.p.) produced a synergistic effect with apomorphine (0.5 microg/kg, i.p., a dopamine D2 receptor agonist), but the pretreatment with fluoxetine (1mg/kg, i.p.) was ineffective to potentiate the effect of apomorphine. Dopamine receptor antagonists or agonists alone or in combination with melatonin did not affect locomotor activity. These results indicate that the antidepressant-like effect of melatonin in the tail suspension test is likely mediated by an interaction with the dopaminergic system, through an activation of dopamine D1 and D2 receptors. Our data confirm the previous notion on the role exerted by melatonin in depression, suggesting that it might be further investigated as an alternative for the management of depression associated with anhedonia.

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