Abstract
Patients with chronic neuropathic pain frequently suffer from symptoms of anhedonia (loss of pleasure), which is a core clinical manifestation of depression. Accumulating studies have shown the beneficial effects of the natural compound sulforaphane (SFN), an activator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), on depression-like phenotype through a potent anti-inflammatory effect. However, it is unknown whether SFN confers beneficial effects in neuropathic pain-associated anhedonia. Spared nerve injury (SNI) is classical rodent model of chronic neuropathic pain. We here used a rat model of SNI. Hierarchical cluster analysis of sucrose preference test (SPT) results was used to classify the SNI rats with or without an anhedonia phenotype. Nrf2 protein expression was significantly decreased in the medial prefrontal cortex (mPFC), hippocampus, spinal cord, and skeletal muscle, but not in the nucleus accumbens, in anhedonia-susceptible rats compared with sham or anhedonia-resistant rats. The expression of Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1), a partner of Nrf2, in mPFC, hippocampus, and muscle of anhedonia-susceptible rats was also significantly lower than that in sham or anhedonia-resilient rats. Subsequent SFN administration after SNI surgery exerted therapeutic effects on reduced mechanical withdrawal threshold (MWT) scores, but not on sucrose preference, through the normalization of Keap1-Nrf2 signaling in the spinal cords of anhedonia-susceptible rats. Interestingly, treatment with SFN 30 min prior to SNI surgery significantly attenuated reduced MWT scores and sucrose preference, and restored tissue Keap1 and Nrf2 levels. In conclusion, this study suggests that decreased Keap1-Nrf2 signaling in mPFC, hippocampus, and muscle may contribute to anhedonia susceptibility post-SNI surgery, and that SFN exerts beneficial effects in SNI rats by normalization of decreased Keap1-Nrf2 signaling.
Highlights
Patients with chronic pain often suffer with depressive symptoms
Post hoc test showed a significant decrease of Keap1 protein in the medial prefrontal cortex (mPFC), hippocampus and muscle in anhedonia-susceptible rats than that of sham and anhedonia-resilient rats (Figures 2A,C,E)
There was a significant decrease of Keap1 protein in the L2-5 spinal cord and liver in anhedonia-susceptible rats than that of sham rats there were no changes in the spinal cord and liver between anhedonia-susceptible and anhedonia-resilient rats (Figures 2D,F)
Summary
Patients with chronic pain often suffer with depressive symptoms. Previous clinical studies have demonstrated that the incidence of comorbid chronic pain and depression is approximately 30 to 50% (Bair et al, 2003; Gustorff et al, 2008; Radat et al, 2013). Comorbid pain and depression are a serious clinical, social, and economic issue that needs to be resolved. Several studies have shown that NSAIDs are not effective in approximately half of patients with chronic pain (White, 2005; Vanegas et al, 2010; Shah and Mehta, 2012). Analgesics and antidepressant agents are currently prescribed for depression in patients with somatic symptoms or chronic pain, drugs without significant side effects are needed for treating the comorbidity of pain and depression
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