Agomelatine: a new opportunity to reduce neuropathic pain. Preclinical evidence.

Antidepressants are first-line treatments of neuropathic pain but not all of these drugs are really effective. Agomelatine is an antidepressant with a novel mode of action, acting as a MT1/MT2 melatonergic receptor agonist and a 5-HT2C receptor antagonist that involves indirect noradrenaline release. Melatonin, serotonin and noradrenaline have been involved in the pathophysiology of neuropathic pain. Yet no study has been conducted to determine agomelatine effects on neuropathic pain in animal models.Using three rat models of neuropathic pain of toxic (oxaliplatin/OXA), metabolic (streptozocin/STZ) and traumatic (sciatic nerve ligation/CCI) etiologies, we investigated the anti-hypersensitivity effect of acute and repeated agomelatine administration. We then determined the influence of melatonergic, 5-HT2C, α-2 and β-1/2 adrenergic receptor antagonists in the anti-hypersensitivity effect of agomelatine. The effect of the combination of agomelatine+gabapentin was evaluated using an isobolographic approach.In STZ and CCI models, single doses of agomelatine significantly and dose-dependently reduced mechanical hypersensitivity. After daily administrations for 2 weeks, this effect was confirmed in the CCI model and agomelatine displayed also a marked anti-hypersensitivity effect in the OXA model. The anti-hypersensitivity effect of agomelatine involved melatonergic, 5-HT2C and α-2 adrenergic receptors but not beta adrenoceptors. The isobolographic analysis demonstrated that the combination of agomelatine+gabapentin had additive effects.Agomelatine exerts a clear-cut anti-hypersensitivity effect in three different neuropathic pain models. Its effect is mediated by melatonergic and 5-HT2C receptors and, even though agomelatine has no affinity, also by α-2 adrenergic receptors. Finally, agomelatine combined with gabapentin produces an additive anti-hypersensitivity effect.