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.

Antidepressant drugs act mainly by blocking the noradrenaline and/or serotonin uptake sites and require a chronic treatment. Tricyclic antidepressants are among the first line treatments clinically recommended against neuropathic pain. As observed against depression, a chronic treatment is required for a therapeutic effect. However, both in depression-related and pain-related research in rodents, it is difficult to design models that reproduce the clinical conditions and are sensitive to chronic but not to acute treatment by antidepressant drugs. In this study, we used a murine neuropathic pain model induced by the unilateral insertion of a polyethylene cuff around the main branch of the sciatic nerve. This model induced a long-lasting ipsilateral mechanical allodynia. We evidenced that chronic, but not acute, treatment with the tricyclic antidepressants nortriptyline or amitriptyline suppressed the cuff-induced mechanical allodynia. On the contrary, fluoxetine, a selective serotonin reuptake inhibitor, remained ineffective. To understand which mechanism is recruited downstream in order to alleviate the allodynia, we tested the opioid receptor antagonist naloxone, the delta-opioid receptor antagonist naltrindole and the kappa-opioid receptor antagonist nor-BNI. We show that the therapeutic effect of notriptyline implicates the endogenous opioid system, in particular the delta- and the kappa-opioid receptors. For comparison, we tested the anticonvulsant gabapentin and showed that it alleviates neuropathic allodynia after 3 days of treatment. Naloxone had no effect on gabapentin therapeutic benefit, showing that antidepressants and anticonvulsants alleviate neuropathic allodynia through independent mechanisms. Our work provides a clinically relevant model to understand the mechanism by which chronic antidepressant treatment can alleviate neuropathic pain.

Background and purpose: Antidepressants are a first-line treatment against neuropathic pain. We previously demonstrated that b2-adrenoceptors are necessary for antidepressants to exert their anti-allodynic action. The aim of the present study was to assess whether b2-adrenoceptor agonists could be sufficient to alleviate neuropathic allodynia. Experimental approach: We used a murine model of neuropathy induced by unilateral sciatic nerve cuffing in C57BL/6J mice. We previously demonstrated that this animal model is sensitive to chronic, but not to acute, treatment with antidepressant drugs, which is clinically relevant. The mechanical allodynia was evaluated using the von Frey filaments. Key results: We showed that chronic but not acute treatment with the b-adrenoceptor agonists, bambuterol, isoprenaline, fenoterol, salbutamol, salmeterol, terbutaline or ritodrine suppressed mechanical allodynia. We confirmed that the action of these b-adrenoceptor agonists was mediated through b2-adrenoceptors by blocking it with intraperitoneal or intrathecal, but not intracerebroventricular or intraplantar, injections of the antagonist ICI118551. We also showed that chronic treatments with the b-adrenoceptor antagonists, propranolol or ICI118551 did not suppress the allodynia. Conclusions and implications:Our data show that chronic treatment with b-adrenoceptor agonists has the same antiallodynic properties as treatments with antidepressant drugs. This study was, however, conducted in an animal model, and a clinical validation will be required to confirm the value of the present findings in patients.

No abstract