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Neurobiol Dis. 2013 Dec;60:39-50. doi: 10.1016/j.nbd.2013.08.012. Epub 2013 Aug 23.

Antidepressants suppress neuropathic pain by a peripheral β2-adrenoceptor mediated anti-TNFα mechanism.

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Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, 67084 Strasbourg, France; Université de Strasbourg, 67084 Strasbourg, France.


Neuropathic pain is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. It is usually chronic and challenging to treat. Some antidepressants are first-line pharmacological treatments for neuropathic pain. The noradrenaline that is recruited by the action of the antidepressants on reuptake transporters has been proposed to act through β2-adrenoceptors (β2-ARs) to lead to the observed therapeutic effect. However, the complex downstream mechanism mediating this action remained to be identified. In this study, we demonstrate in a mouse model of neuropathic pain that an antidepressant's effect on neuropathic allodynia involves the peripheral nervous system and the inhibition of cytokine tumor necrosis factor α (TNFα) production. The antiallodynic action of nortriptyline is indeed lost after peripheral sympathectomy, but not after lesion of central descending noradrenergic pathways. More particularly, we report that antidepressant-recruited noradrenaline acts, within dorsal root ganglia, on β2-ARs expressed by non-neuronal satellite cells. This stimulation of β2-ARs decreases the neuropathy-induced production of membrane-bound TNFα, resulting in relief of neuropathic allodynia. This indirect anti-TNFα action was observed with the tricyclic antidepressant nortriptyline, the selective serotonin and noradrenaline reuptake inhibitor venlafaxine and the β2-AR agonist terbutaline. Our data revealed an original therapeutic mechanism that may open novel research avenues for the management of painful peripheral neuropathies.


Adrenoceptor; Allodynia; Antidepressant; Arbp; CGRP; Cytokine; Dorsal root ganglia; GS; IL; NF200; NP; Neuropathy; Noradrenergic; Pain; Satellite; TCA; TH; TNFα; acidic ribosomal phosphoprotein P0; calcitonin gene related peptide; glutamine synthetase; interleukin; neurofilament 200; neuropathic pain group; tricyclic antidepressant; tumor necrosis factor α; tyrosine hydroxylase; β2-AR; β2-adrenoceptor

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