A single centre, parallel group pilot study to investigate the effect of opioids on immunomarkers using gene expression profiling
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Background: The effects of morphine on immune cells include reduced NK cell cytotoxicity and reduced lymphocyte proliferation but human prospective in vivo clinical research has been inconclusive. This study aims to define the changes in intraoperative lymphocyte gene expression in patients receiving morphine. Methods: mRNA gene expression was analysed in CD4+, CD8+ and NK cells from 40 patients undergoing gynaecological laparotomies, using the 3’ Affymetrix microarray. Patients matched by BMI, age, operation duration and pain levels received morphine or control analgesia. Genes demonstrating differential expression (fold change≥±2; p-value≤0.05) following ANOVA were further investigated. Gene expression analysis was confirmed functionally through investigation of serum cytokine concentration (cytometric bead array), serum cortisol concentration (ELISA) and NK cell cytotoxicity (NK cell degranulation assay). Finally, statistical analyses were performed to evaluate the relative importance of individual genes highlighted following analysis. Results: Microarray analysis identified differential expression of 450 unique genes by morphine at 2 hour and 460 unique genes by oxycodone at 6 hour. Genes were transiently deregulated by morphine and enriched in processes suggestive of lymphocyte anergy. Genes induced by oxycodone were subject to a more sustained deregulation and enriched in processes related to normal immune functioning. Greater increases in IL-6 and IL-10 concentrations were induced by morphine, supportive of a greater TH2 shift. NK cell degranulation results were inconclusive and should be repeated with more samples. Cortisolconcentration did not significantly change between timepoints. Statistical analyses suggested that AGPAT3, TPK1 and TIAM1 might be important in mediating morphine-induced changes. Conclusion: This study demonstrates altered lymphocyte gene expression in patients receiving intraoperative morphine compared to control analgesia. The greater morphine-induced TH2 shift suggested by gene expression analysis was confirmed functionally, consistent with and extending current knowledge of morphine-induced immunosuppression.
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