Chronic, but not acute, tricyclic antidepressant treatment alleviates neuropathic allodynia after sciatic nerve cuffing in mice

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.