β2-Adrenoceptors Are Critical for Antidepressant Treatment of Neuropathic Pain

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 beta(2)-AR was evaluated by studying beta(2)-AR(-/-) mice. We used von Frey filaments to assess mechanical allodynia. Results: The antiallodynic action of nortriptyline was not affected by cotreatment with the alpha(2)-AR antagonist yohimbine, the beta(1)-AR antagonists atenolol or metoprolol, or the beta(3)-AR antagonist SR 59230A. On the contrary, the beta-AR antagonists propranolol or sotalol, the beta(1)/beta(2)-AR antagonists alprenolol or pindolol, or the specific beta(2)-AR antagonist ICI 118,551 blocked the action of nortriptyline. The effect of nortriptyline was also totally absent in beta(2)-AR-deficient mice. Interpretation: Stimulation of beta(2)-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 beta-blockers that affect beta(2)-AR and antidepressant drugs in patients treated for neuropathic pain.