Pharmacological inhibition of soluble epoxide hydrolase alleviates chronic neuropathic pain induced anhedonia symptoms: differential role of AhR and TSPO signaling

Abstract

Patients who suffer from chronic pain have a higher incidence to develop depression, which needs effective treatments. TPPU, a soluble epoxide hydrolase (sEH) inhibitor, was reported to have analgesia and antidepressant effects in animal models, suggesting its potential improvement in this comorbidity. Here, we sought to investigate: (1) the occurrence of anhedonia symptoms in mice with chronic neuropathic pain and the sEH protein expression in different tissues, including central nervous system and peripheral tissues; (2) the effects of TPPU on nociceptive and anhedonia behaviors in anhedonia susceptible mice, and (3) the involvement of Aryl hydrocarbon receptor (AhR) signaling and translocator protein (TSPO) signaling as possible targets for this comorbidity. Spared nerve injury (SNI) was constructed to mimic chronic neuropathic pain (CNP) model, and that mice in SNI group were classified into chronic pain with or without anhedonia phenotype via hierarchical cluster analysis of sucrose preference test (SPT) results. Protein levels of sEH were increased in medial prefrontal cortex (mPFC), hippocampus, spinal cord, liver, kidney and gut, but not in anterior cingulate cortex (ACC), nucleus accumbens (NAc), striatum, cerebellum, heart, muscle and vessel in anhedonia susceptible mice as compared with sham or anhedonia resilient mice. Chronic treatment with TPPU (3 mg/kg, orally, once per day for 7 days) improved withdraw threshold and SPT scores in anhedonia susceptible mice. Interestingly, the antidepressant, but not analgesia effect, of TPPU seems to be pharmacologically abrogated by pretreatment with AhR agonist (FICZ, orally, 100 μg/kg) via regulating inflammatory cytokines and CYP1A1 levels in the serum as well as neuroinflammation in the microglia and astrocytes. Interestingly, the classical TSPO pathway, a crucial factor in the analgesia and antidepressant effects of TPPU, failed to show any difference in subjects who were treated with drugs targeted at the AhR. Collectively, our findings indicate that TPPU may alleviate depression‐like symptoms in CNP mice through two independent pathways: (1) the direct antidepressant effects via regulating neuroinflammation mediated by AhR, and (2) the improvement of allodynia and depressive symptoms via the TSPO signaling and downstream neurosteroids. Thus, AhR provides a potential therapeutic target for treatment of depression induced by chronic pain, and strategies targeting TSPO signaling could be a vital approach to alleviate the comorbidity of chronic pain and depression.Support or Funding InformationThis work was supported , in part, by grants from the National Natural Science Foundation of China (to A.L., 81771159 and 81571047; to C.Y., 81703482)The overview of our manuscript.Figure 1