Thalidomide reduces mechanical hyperalgesia and depressive-like behavior induced by peripheral nerve crush in mice

Abstract Background: It has been shown that chronic pain is able to induce depressive disorders in humans, in part, due to peripheral inflammation that reaches the central nervous system. However, the mechanisms involved remain to be established. The purpose of this study was to investigate whether sciatic nerve crush could produce depression-like behaviors, in addition to pain-related behaviors, in mice. Once confirmed, this model was used to investigate tumor necrosis factor-α (TNF-α) as a key mediator involved in the pathophysiology of both pain and depression. Experimental approach: Male Swiss mice were divided into three groups, naive, sham and operated. In the operated group, the sciatic nerve was crushed. Following surgery, animals from the operated group were treated daily by oral gavage (p.o.) with saline (10 ml/kg), fluoxetine (20 mg/kg) or thalidomide (10 mg/kg) for 15 days. Mechanical hyperalgesia was evaluated every 3 days by von Frey filaments and depressive-like behavior was assessed at the end of day 15, using the tail suspension test (TST) and the forced swimming test (FST). Then, samples from the prefrontal cortex, hippocampus and sciatic nerve were processed to measure TNF-α levels by enzyme-linked immunosorbent assay (ELISA). Results: Crush caused significant mechanical hyperalgesia and depressive-like behaviors and increased TNF-α levels in the sciatic nerve, prefrontal cortex and hippocampus of operated animals. Treatment with fluoxetine or thalidomide reversed crush-induced mechanical hyperalgesia, depressive-like behaviors and the increased TNF-α levels in the sciatic nerve, prefrontal cortex and hippocampus. Conclusions: The sciatic nerve crush model represents a good model to study to mechanisms underlying both pain and depressive-like behaviors. Furthermore, inhibitors of TNF-α synthesis, like thalidomide, have a potential to treat depressive disorders associated with neuropathic pain.