beta(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 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.


CONCLUSIONS
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.
Yalcin
Ipek
I
Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique and Université de Strasbourg, France.
Choucair-Jaafar
Nada
N
Benbouzid
Malika
M
Tessier
Luc-Henri
LH
Muller
André
A
Hein
Lutz
L
Freund-Mercier
Marie-José
MJ
Barrot
Michel
M
D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use; D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement; D018343:Receptors, Adrenergic, beta-2 / Q000172:deficiency / Q000502:physiology*; D012585:Sciatica / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D013997:Time Factors
D018759:Adrenergic Uptake Inhibitors; D000317:Adrenergic alpha-Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D000929:Antidepressive Agents, Tricyclic; D018343:Receptors, Adrenergic, beta-2