title: Agomelatine: a new opportunity to reduce neuropathic pain-preclinical evidence.
abstract: Antidepressants are first-line treatments of neuropathic pain but not all these drugs are really effective. Agomelatine is an antidepressant with a novel mode of action, acting as an MT1/MT2 melatonergic receptor agonist and a 5-HT2C receptor antagonist that involves indirect norepinephrine release. Melatonin, serotonin, and norepinephrine 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 3 rat models of neuropathic pain of toxic (oxaliplatin/OXA), metabolic (streptozocin/STZ), and traumatic (sciatic nerve ligation/CCI [chronic constriction nerve injury]) etiologies, we investigated the antihypersensitivity 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 antihypersensitivity 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 also displayed a marked antihypersensitivity effect in the OXA model. The antihypersensitivity 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 antihypersensitivity effect in 3 different neuropathic pain models. Its effect is mediated by melatonergic and 5-HT2C receptors and, although agomelatine has no affinity, also by α-2 adrenergic receptors. Finally, agomelatine combined with gabapentin produces an additive antihypersensitivity effect.
authors.affiliation: Université Clermont Auvergne, Université d'Auvergne, INSERM UMR 1107 Neuro-Dol Equipe Pharmacologie Fondamentale et Clinique de la Douleur, CHU Clermont-Ferrand Service de Pharmacologie Médicale, Institut Analgesia, Faculté de Médecine, Clermont-Ferrand, France.
authors.forename: Chouki
authors.initials: C
authors.lastname: Chenaf
authors.affiliation: Université Clermont Auvergne, Université d'Auvergne, INSERM UMR 1107 Neuro-Dol Equipe Pharmacologie Fondamentale et Clinique de la Douleur, Institut Analgesia, Faculté de Médecine, Clermont-Ferrand, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Chapuy
authors.affiliation: Université Clermont Auvergne, Université d'Auvergne, INSERM UMR 1107 Neuro-Dol Equipe Pharmacologie Fondamentale et Clinique de la Douleur, CHU Clermont-Ferrand Service de Pharmacologie Médicale, Institut Analgesia, Faculté de Médecine, Clermont-Ferrand, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Libert
authors.affiliation: Université Clermont Auvergne, Université d'Auvergne, INSERM UMR 1107 Neuro-Dol Equipe Pharmacologie Fondamentale et Clinique de la Douleur, Institut Analgesia, Faculté de Médecine, Clermont-Ferrand, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Marchand
authors.affiliation: Université Clermont Auvergne, Université d'Auvergne, INSERM UMR 1107 Neuro-Dol Equipe Pharmacologie Fondamentale et Clinique de la Douleur, Institut Analgesia, Faculté de Médecine, Clermont-Ferrand, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Courteix
authors.affiliation: Neuropsychiatry Division, Institut de Recherches Internationales Servier, Suresnes, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Bertrand
authors.affiliation: Neuropsychiatry Division, Institut de Recherches Internationales Servier, Suresnes, France.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gabriel
authors.affiliation: Neuropsychiatry Division, Institut de Recherches Internationales Servier, Suresnes, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mocaër
authors.affiliation: Université Clermont Auvergne, Université d'Auvergne, INSERM UMR 1107 Neuro-Dol Equipe Pharmacologie Fondamentale et Clinique de la Douleur, CHU Clermont-Ferrand Service de Pharmacologie Médicale, Institut Analgesia, Faculté de Médecine, Clermont-Ferrand, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Eschalier
authors.affiliation: Université Clermont Auvergne, Université d'Auvergne, INSERM UMR 1107 Neuro-Dol Equipe Pharmacologie Fondamentale et Clinique de la Douleur, CHU Clermont-Ferrand Service de Pharmacologie Médicale, Institut Analgesia, Faculté de Médecine, Clermont-Ferrand, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Authier
mesh_terms: D000081:Acetamides / Q000627:therapeutic use*; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000627:therapeutic use; D000588:Amines / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D003251:Constriction, Pathologic / Q000150:complications; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D000077206:Gabapentin; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D006993:Hypnotics and Sedatives / Q000627:therapeutic use*; D019329:Idazoxan / Q000627:therapeutic use; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology; D009944:Organoplatinum Compounds / Q000633:toxicity; D000077150:Oxaliplatin; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000627:therapeutic use; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D058669:Adrenergic alpha-2 Receptor Antagonists; D000588:Amines; D000970:Antineoplastic Agents; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D000077206:Gabapentin; D006993:Hypnotics and Sedatives; D019329:Idazoxan; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D013876:Thiophenes; D005680:gamma-Aminobutyric Acid; C120267:S 22153; C084711:agomelatine; D009281:Naphthalenes