title: Antidepressants suppress neuropathic pain by a peripheral β2-adrenoceptor mediated anti-TNFα mechanism.
abstract: 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.
authors: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, 67084 Strasbourg, France; Université de Strasbourg, 67084 Strasbourg, France.
authors: Yohann
authors: Y
authors: Bohren
authors: Luc-Henri
authors: LH
authors: Tessier
authors: Salim
authors: S
authors: Megat
authors: Hugues
authors: H
authors: Petitjean
authors: Sylvain
authors: S
authors: Hugel
authors: Dorothée
authors: D
authors: Daniel
authors: Mélanie
authors: M
authors: Kremer
authors: Sylvie
authors: S
authors: Fournel
authors: Lutz
authors: L
authors: Hein
authors: Rémy
authors: R
authors: Schlichter
authors: Marie-José
authors: MJ
authors: Freund-Mercier
authors: Ipek
authors: I
authors: Yalcin
authors: Michel
authors: M
authors: Barrot
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology* / Q000627:therapeutic use; D000068800:Etanercept; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000473:pathology; D007074:Immunoglobulin G / Q000494:pharmacology; D000069285:Infliximab; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D009661:Nortriptyline / Q000494:pharmacology; D010147:Pain Measurement; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D000929:Antidepressive Agents, Tricyclic; D007074:Immunoglobulin G; D018343:Receptors, Adrenergic, beta-2; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D009661:Nortriptyline; D000068800:Etanercept; D009638:Norepinephrine
keywords: 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