title: Antidepressants and gabapentinoids in neuropathic pain: Mechanistic insights.
abstract: Neuropathic pain arises as a consequence of a lesion or disease affecting the somatosensory system. It is generally chronic and challenging to treat. The recommended pharmacotherapy for neuropathic pain includes the use of some antidepressants, such as tricyclic antidepressants (TCAs) (amitriptyline…) or serotonin and noradrenaline re-uptake inhibitors (duloxetine…), and/or anticonvulsants such as the gabapentinoids gabapentin or pregabalin. Antidepressant drugs are not acute analgesics but require a chronic treatment to relieve neuropathic pain, which suggests the recruitment of secondary downstream mechanisms as well as long-term molecular and neuronal plasticity. Noradrenaline is a major actor for the action of antidepressant drugs in a neuropathic pain context. Mechanistic hypotheses have implied the recruitment of noradrenergic descending pathways as well as the peripheral recruitment of noradrenaline from sympathetic fibers sprouting into dorsal root ganglia; and importance of both α2 and β2 adrenoceptors have been reported. These monoamine re-uptake inhibitors may also indirectly act as anti-proinflammatory cytokine drugs; and their therapeutic action requires the opioid system, particularly the mu (MOP) and/or delta (DOP) opioid receptors. Gabapentinoids, which target the voltage-dependent calcium channels α2δ-1 subunit, inhibit calcium currents, thus decreasing the excitatory transmitter release and spinal sensitization. Gabapentinoids also activate the descending noradrenergic pain inhibitory system coupled to spinal α2 adrenoceptors. Gabapentinoid treatment may also indirectly impact on neuroimmune actors, like proinflammatory cytokines. These drugs are effective against neuropathic pain both with acute administration at high dose and with repeated administration. This review focuses on mechanistic knowledge concerning chronic antidepressant treatment and gabapentinoid treatment in a neuropathic pain context.
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Kremer
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France; Centre d'Etude et de Traitement de la Douleur, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Salvat
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France; Centre d'Etude et de Traitement de la Douleur, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: André
authors.initials: A
authors.lastname: Muller
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France.
authors.forename: Ipek
authors.initials: I
authors.lastname: Yalcin
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France. Electronic address: mbarrot@inci-cnrs.unistra.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Barrot
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009437:Neuralgia / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000700:Analgesics; D000928:Antidepressive Agents; D005680:gamma-Aminobutyric Acid
keywords: antidepressants; gabapentinoids; monoaminergic system; neuroimmune; neuropathic pain; opioidergic system