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: Yohann Bohren, Luc-Henri Tessier, Salim Megat, Hugues Petitjean, Sylvain Hugel, Dorothée Daniel, Mélanie Kremer, Sylvie Fournel, Lutz Hein, Rémy Schlichter, Marie-José Freund-Mercier, Ipek Yalcin, Michel Barrot
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 60 Pg. 39-50 (Dec 2013) ISSN: 1095-953X [Electronic] United States
• PMID: 23978467 (Publication Type: Journal Article)
• Copyright: © 2013.

Chemical References

• Adrenergic beta-2 Receptor Agonists
• Anti-Inflammatory Agents, Non-Steroidal
• Antibodies, Monoclonal
• Antidepressive Agents, Tricyclic
• Immunoglobulin G
• Receptors, Adrenergic, beta-2
• Receptors, Tumor Necrosis Factor
• Tumor Necrosis Factor-alpha
• Infliximab
• Nortriptyline
• Etanercept
• Norepinephrine

Topics

• Adrenergic beta-2 Receptor Agonists (pharmacology)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Antibodies, Monoclonal (pharmacology)
• Antidepressive Agents, Tricyclic (pharmacology, therapeutic use)
• Etanercept
• Ganglia, Spinal (metabolism, pathology)
• Immunoglobulin G (pharmacology)
• Infliximab
• Male
• Mice
• Mice, Inbred C57BL
• Neuralgia (drug therapy, metabolism)
• Norepinephrine (metabolism)
• Nortriptyline (pharmacology)
• Pain Measurement
• Receptors, Adrenergic, beta-2 (metabolism)
• Receptors, Tumor Necrosis Factor
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)