2. Academic Validation
  3. The soluble epoxide hydrolase inhibitor TPPU improves comorbidity of chronic pain and depression via the AHR and TSPO signaling

The soluble epoxide hydrolase inhibitor TPPU improves comorbidity of chronic pain and depression via the AHR and TSPO signaling

  • J Transl Med. 2023 Feb 2;21(1):71. doi: 10.1186/s12967-023-03917-x.
Ailin Luo # 1,  Zifeng Wu # 2,  Shan Li # 1,  Cindy B McReynolds 3,  Di Wang 2,  Hanyu Liu 2,  Chaoli Huang 2 4,  Teng He 2,  Xinying Zhang 2,  Yuanyuan Wang 2,  Cunming Liu 2,  Bruce D Hammock 5,  Kenji Hashimoto 6,  Chun Yang 7
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 2 Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
  • 3 Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California, Davis, CA, 95616, USA.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Nanjing University, Nanjing, 210061, China.
  • 5 Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California, Davis, CA, 95616, USA. bdhammock@ucdavis.edu.
  • 6 Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan. hashimoto@faculty.chiba-u.jp.
  • 7 Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. chunyang@njmu.edu.cn.
  • # Contributed equally.
PMID: 36732752 DOI: 10.1186/s12967-023-03917-x
Abstract

Background: Patients suffering from chronic pain often also exhibit depression symptoms. Soluble Epoxide Hydrolase (sEH) inhibitors can decrease blood levels of inflammatory cytokines. However, whether inhibiting sEH signaling is beneficial for the comorbidity of pain and depression is unknown.

Methods: According to a sucrose preference test (SPT), spared nerve injury (SNI) mice were classified into pain with or without an anhedonia phenotype. Then, sEH protein expression and inflammatory cytokines were assessed in selected tissues. Furthermore, we used sEH inhibitor TPPU to determine the role of sEH in chronic pain and depression. Importantly, agonists and antagonists of Aryl Hydrocarbon Receptor (AHR) and translocator protein (TSPO) were used to explore the pathogenesis of sEH signaling.

Results: In anhedonia-susceptible mice, the tissue levels of sEH were significantly increased in the medial prefrontal cortex (mPFC), hippocampus, spinal cord, liver, kidney, and gut. Importantly, serum CYP1A1 and inflammatory cytokines, such as interleukin 1β (IL-1β) and the tumor necrosis factor α (TNF-α), were increased simultaneously. TPPU improved the scores of mechanical withdrawal threshold (MWT) and SPT, and decreased the levels of serum CYP1A1 and inflammatory cytokines. AHR antagonist relieved the anhedonia behaviors but not the algesia behaviors in anhedonia-susceptible mice, whereas an AHR agonist abolished the antidepressant-like effect of TPPU. In addition, a TSPO agonist exerted a similar therapeutic effect to that of TPPU, whereas pretreatment with a TSPO antagonist abolished the antidepressant-like and analgesic effects of TPPU.

Conclusions: sEH underlies the mechanisms of the comorbidity of chronic pain and depression and that TPPU exerts a beneficial effect on anhedonia behaviors in a pain model via AHR and TSPO signaling.

Keywords

Aryl hydrocarbon receptor; Chronic pain; Depression; Soluble epoxide hydrolase; TPPU; Translocator protein.

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