Antidepressants suppress neuropathic pain by a peripheral beta2-adrenoceptor mediated anti-TNFalpha mechanism.

  • Bohren Y
  • Tessier L
  • Megat S
 et al. 
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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 beta2-adrenoceptors (beta2-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 alpha (TNFalpha) 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 beta2-ARs expressed by non-neuronal satellite cells. This stimulation of beta2-ARs decreases the neuropathy-induced production of membrane-bound TNFalpha, resulting in relief of neuropathic allodynia. This indirect anti-TNFalpha action was observed with the tricyclic antidepressant nortriptyline, the selective serotonin and noradrenaline reuptake inhibitor venlafaxine and the beta2-AR agonist terbutaline. Our data revealed an original therapeutic mechanism that may open novel research avenues for the management of painful peripheral neuropathies.

Author-supplied keywords

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

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  • Yohann Bohren

  • Luc-Henri Tessier

  • Salim Megat

  • Hugues Petitjean

  • Sylvain Hugel

  • Dorothee Daniel

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