Research progress of p38 as a new therapeutic target against morphine tolerance and the current status of therapy of morphine tolerance

Xiao, Fu; Zhang, Yanhong

doi:10.1080/1061186x.2022.2138895

Cited by 2 publications

(1 citation statement)

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“…However, the chronic administration of morphine inevitably leads to various undesirable effects such as morphine tolerance (MT) and dependence, respiratory depression, nausea, vomiting, and sedation, which pose challenges to its clinical application ( Ouyang et al, 2022 ). The development of morphine tolerance is a complex and multifaceted process, encompassing various factors such as the desensitization and internalization of opioid receptors ( Narita et al, 2006 ), the formation of heterodimers between G protein-coupled receptors ( Szentirmay et al, 2013 ), activation of glial cells, modifications in glutamate receptor function ( Wang et al, 2021 ), stimulation of the cyclic adenosine monophosphate (cAMP) pathway ( Coffey et al, 2022 ) and mitogen-activated protein kinase (MAPK) pathway ( Fu and Zhang, 2023 ), among others. Considering the inadequate therapeutic outcomes and significant burden associated with morphine tolerance, it is imperative to identify potential underlying risk factors that contribute to its occurrence.…”

Section: Introductionmentioning

confidence: 99%

Genetically supported causality between gut microbiota, immune cells and morphine tolerance: a two-sample Mendelian randomization study

Han,

Gao,

Wang

et al. 2024

Front. Microbiol.

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BackgroundPrevious researches have suggested a significant connection between the gut microbiota/immune cells and morphine tolerance (MT), but there is still uncertainty regarding their causal relationship. Hence, our objective is to inverstigate this causal association and reveal the impact of gut microbiota/immune cells on the risk of developing MT using a two-sample Mendelian randomization (MR) study.MethodsWe conducted a comprehensive analysis using genome-wide association study (GWAS) summary statistics for gut microbiota, immune cells, and MT. The main approach employed was the inverse variance-weighted (IVW) method in MR. To assess horizontal pleiotropy and remove outlier single-nucleotide polymorphisms (SNPs), we utilized the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) technique as well as MR-Egger regression. Heterogeneity detection was performed using Cochran’s Q-test. Additionally, leave-one-out analysis was carried out to determine if any single SNP drove the causal association signals. Finally, we conducted a reverse MR to evaluate the potential of reverse causation.ResultsWe discovered that 6 gut microbial taxa and 16 immune cells were causally related to MT (p < 0.05). Among them, 2 bacterial features and 9 immunophenotypes retained a strong causal relationship with lower risk of MT: genus. Lachnospiraceae NK4A136group (OR: 0.962, 95% CI: 0.940–0.987, p = 0.030), genus. RuminococcaceaeUCG011 (OR: 0.960, 95% CI: 0.946–0.976, p = 0.003), BAFF-R on B cell (OR: 0.972, 95% CI: 0.947–0.998, p = 0.013). Furthermore, 4 bacterial features and 7 immunophenotypes were identified to be significantly associated with MT risk: genus. Flavonifractor (OR: 1.044, 95% CI: 1.017–1.069, p = 0.029), genus. Prevotella9 (OR: 1.054, 95% CI: 1.020–1.090, p = 0.037), B cell % CD3-lymphocyte (OR: 1.976, 95% CI: 1.027–1.129, p = 0.026). The Cochrane’s Q test revealed no heterogeneity (p > 0.05). Furthermore, the MR-Egger and MR-PRESSO analyses reveal no instances of horizontal pleiotropy (p > 0.05). Besides, leave-one-out analysis confirmed the robustness of MR results. After adding BMI to the multivariate MR analysis, the gut microbial taxa and immune cells exposure-outcome effect were attenuated.ConclusionOur research confirm the potential link between gut microbiota and immune cells with MT, shedding light on the mechanism by which gut microbiota and immune cells may contribute to MT. These findings lay the groundwork for future investigations into targeted prevention strategies.

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Section: Introductionmentioning

confidence: 99%

Genetically supported causality between gut microbiota, immune cells and morphine tolerance: a two-sample Mendelian randomization study

Han,

Gao,

Wang

et al. 2024

Front. Microbiol.

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Effect of NLRP3 inflammasome induced astrocyte phenotype alteration in morphine tolerance

Yuan,

Lu,

Zhang

et al. 2024

Front. Pharmacol.

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IntroductionMorphine is a widely used analgesic, but its prolonged use often leads to tolerance, limiting its therapeutic efficacy. Research implicates the NLRP3 inflammasome and reactive astrocytes in the development of morphine tolerance, with reactive astrocytes classified into A1 neurotoxic and A2 neuroprotective phenotypes. This study explores the role of the NLRP3 inflammasome and the transformation of astrocyte phenotypes in the progression of morphine tolerance.MethodsA model of morphine tolerance was established by administering morphine intrathecally for seven consecutive days. To inhibit NLRP3 inflammasome activation, we coadministered MCC950, a selective NLRP3 inhibitor. Thermal withdrawal latency was used to assess tolerance development. Protein and mRNA levels of GFAP, IL-18, NLRP3, C3 (A1 marker), and S100A10 (A2 marker) in the spinal cord were measured using Western blotting (WB) and real-time quantitative polymerase chain reaction (RT-qPCR). Immunofluorescence was employed to assess the colocalization of C3 and GFAP.ResultsSeven days of morphine administration induced tolerance, which was associated with increased levels of GFAP, IL-18, NLRP3, and C3, and a decreased level of S100A10. Coadministration of morphine and MCC950 significantly slowed the development of morphine tolerance and reversed changes in NLRP3, IL-18, GFAP, C3, and S100A10 protein levels.DiscussionOur findings indicate a significant link between NLRP3 inflammasome activation and morphine tolerance, suggesting that NLRP3 contributes to the transformation of astrocytes to the A1 phenotype. Inhibiting NLRP3 inflammasome activation holds promise in reversing astrocyte phenotype changes, potentially mitigating morphine tolerance.

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Research progress of p38 as a new therapeutic target against morphine tolerance and the current status of therapy of morphine tolerance

Cited by 2 publications

References 180 publications

Genetically supported causality between gut microbiota, immune cells and morphine tolerance: a two-sample Mendelian randomization study

Genetically supported causality between gut microbiota, immune cells and morphine tolerance: a two-sample Mendelian randomization study

Effect of NLRP3 inflammasome induced astrocyte phenotype alteration in morphine tolerance

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