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β2-adrenoceptors are critical for antidepressant treatment of neuropathic pain

Authors

  • Ipek Yalcin PharmD, PhD,

    1. Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique and Université de Strasbourg, Strasbourg, France
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    • I.Y. and N.C.-J. equally contributed to this work.

  • Nada Choucair-Jaafar PhD,

    1. Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique and Université de Strasbourg, Strasbourg, France
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    • I.Y. and N.C.-J. equally contributed to this work.

  • Malika Benbouzid PhD,

    1. Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique and Université de Strasbourg, Strasbourg, France
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    • M. Benhouzid was supported by a Présidence fellowship from the Université Louis Pasteur.

  • Luc-Henri Tessier PhD,

    1. Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique and Université de Strasbourg, Strasbourg, France
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  • André Muller MD, PhD,

    1. Centre de la Douleur, Hôpitaux Universitaires, Strasbourg, France
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  • Lutz Hein PhD,

    1. Institute of Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany
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  • Marie-José Freund-Mercier PhD,

    1. Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique and Université de Strasbourg, Strasbourg, France
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  • Michel Barrot PhD

    Corresponding author
    1. Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique and Université de Strasbourg, Strasbourg, France
    • Département Nociception et Douleur, Institut des Neurosciences Cellulaires et Intégratives, 21 rue Descartes, 67084 Strasbourg cedex, France
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  • Potential conflict of interest: Nothing to report.

Abstract

Objective

Tricyclic antidepressants (TCAs) are one of the first-line pharmacological treatments against neuropathic pain. TCAs increase the extracellular concentrations of noradrenaline and serotonin by blocking the reuptake transporters of these amines. However, the precise downstream mechanism leading to the therapeutic action remains identified. In this work, we evaluated the role of adrenergic receptors (ARs) in the action of TCAs.

Methods

We used pharmacological and genetic approaches in mice to study the role of ARs in the antiallodynic action of the TCA nortriptyline. Peripheral neuropathy was induced by the insertion of a polyethylene cuff around the main branch of the sciatic nerve. The specific role of β2-AR was evaluated by studying β2-AR−/− mice. We used von Frey filaments to assess mechanical allodynia.

Results

The antiallodynic action of nortriptyline was not affected by cotreatment with the α2-AR antagonist yohimbine, the β1-AR antagonists atenolol or metoprolol, or the β3-AR antagonist SR 59230A. On the contrary, the β-AR antagonists propranolol or sotalol, the β12-AR antagonists alprenolol or pindolol, or the specific β2-AR antagonist ICI 118,551 blocked the action of nortriptyline. The effect of nortriptyline was also totally absent in β2-AR–deficient mice.

Interpretation

Stimulation of β2-AR is necessary for nortriptyline to exert its antiallodynic action against neuropathic pain. These findings provide new insight into the mechanism by which antidepressants alleviate neuropathic pain. Our results also raise the question of a potential incompatibility between β-blockers that affect β2-AR and antidepressant drugs in patients treated for neuropathic pain. Ann Neurol 2009;65:218–225

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