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

Journal of Translational Medicine, 2023 · DOI: https://doi.org/10.1186/s12967-023-03917-x · Published: January 23, 2023

Simple Explanation

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. 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. 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.

Study Duration

Not specified

Participants

Two month-old male C57BL/6 mice

Evidence Level

Not specified

Key Findings

1
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.
2
TPPU improved the scores of mechanical withdrawal threshold (MWT) and SPT, and decreased the levels of serum CYP1A1 and inflammatory cytokines.
3
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.

Research Summary

Our present study results suggest that elevated levels of sEH play an important role in neuropathic pain with anhedonia(Fig. 6). Moreover, TPPU may alleviate the anhedonia and pain behaviors in two ways: (1) reducing the release of peripheral inflammatory factors via the inhibition of AHR signaling, to function as an antidepressant; and (2) improving depressive-like and hyperalgesic behaviors by promoting the synthesis of neurosteroids involved in TSPO signaling. Therefore, these findings provide novel therapeutic targets for chronic pain and depression comorbidity.

Practical Implications

Therapeutic Target

sEH is a potential therapeutic target for managing chronic pain and depression comorbidity.

Treatment Strategy

TPPU, by inhibiting sEH, may serve as a treatment to alleviate anhedonia and pain behaviors.

Signaling Pathways

AHR and TSPO signaling pathways are crucial in the alleviation of pain-depression comorbidity using sEH inhibitors.

Study Limitations

1
The study is limited to mice models and may not directly translate to humans.
2
The precise mechanisms by which sEH influences AHR and TSPO signaling require further investigation.
3
Further research is needed to explore other potential agents for chronic pain and depression comorbidity.

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