Role of Keap1-Nrf2 Signaling in Anhedonia Symptoms in a Rat Model of Chronic Neuropathic Pain: Improvement With Sulforaphane

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.