β 2 ‐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 2-AR was evaluated by studying 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 2-AR antagonist yohimbine, the 1-AR antagonists atenolol or metoprolol, or the 3-AR antagonist SR 59230A. On the contrary, the -AR antagonists propranolol or sotalol, the 1/2-AR antagonists alprenolol or pindolol, or the specific 2-AR antagonist ICI 118,551 blocked the action of nortriptyline. The effect of nortriptyline was also totally absent in 2-AR-deficient mice. Interpretation Stimulation of 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 -blockers that affect 2-AR and antidepressant drugs in patients treated for neuropathic pain. Ann Neurol 2009; 65:218-225.