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BackgroundPatients 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.MethodsAccording 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.ResultsIn 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.ConclusionssEH 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.

BackgroundThe brain-gut-microbiota axis plays a crucial role in the bidirectional interactions between the brain and the gut. Soluble epoxide hydrolase (coded by the Ephx2 gene) plays an important role in inflammation, which has been implicated in stress-related depression. Ephx2 knock-out (KO) mice exposed to chronic social defeat stress (CSDS) did not show depression-like behaviors, indicating stress resilience. Here we examined whether the brain-gut-microbiota axis influences the resilience in Ephx2 KO mice.MethodsEffects of fecal microbiota transplantation (FMT) from CSDS-susceptible (or control) mice in wild-type (WT) mice and Ephx2 KO mice treated with an antibiotic cocktail (ABX) were investigated. Behavioral, biochemical tests and 16S ribosome RNA analysis were performed.ResultsFMT from CSDS-susceptible mice produced anhedonia-like behavior in ABX-treated WT and Ephx2 KO mice. The 16S ribosome RNA analysis showed that Faecalibaculum rodentium (F. rodentium) may be responsible for the observed anhedonia-like behavior following FMT from CSDS-susceptible mice. Ingestion of F. rodentium for 14 days produced depression- and anhedonia-like behaviors, higher blood levels of interleukin-6, and reduced expression of synaptic proteins in the prefrontal cortex of ABX-treated Ephx2 KO mice. Furthermore, subdiaphragmatic vagotomy blocked the development of these behavioral abnormalities after ingestion of F. rodentium.LimitationsDetailed mechanisms are unclear.ConclusionsThese findings suggest that F. rodentium might contribute to the conversion of resilient Ephx2 KO mice into KO mice with depression-like phenotypes. The brain-gut-microbiota axis via the subdiaphragmatic vagus nerve plays a crucial role in susceptibility and resilience to stress.

ObjectiveExposure to the herbicide glyphosate during pregnancy and lactation may increase the risk for autism spectrum disorder (ASD) in offspring. Recently, we reported that maternal exposure of formulated glyphosate caused ASD-like behaviors in juvenile offspring. Here, we investigated whether maternal exposure of pure glyphosate could cause ASD-like behaviors in juvenile offspring.MethodsWater or 0.098% glyphosate was administered as drinking water from E5 to P21 (weaning). Behavioral tests such as grooming test and three-chamber social interaction test in male offspring were performed from P28 to P35.ResultsMale offspring showed ASD-like behavioral abnormalities (i.e., increasing grooming behavior and social interaction deficit) after maternal exposure of glyphosate.ConclusionThe findings suggest that the exposure of glyphosate during pregnancy and lactation may cause ASD-like behavioral abnormalities in male juvenile offspring. It is likely that glyphosate itself, but not the other ingredients, may contribute to ASD-like behavioral abnormalities in juvenile offspring.