Suppression of Human Natural Killer Cells by Different Classes of Opioids

BACKGROUND: The use of regional and other opioid-sparing forms of anesthesia has been associated with a decrease in the recurrence of certain malignancies. Direct suppression of human natural killer cells by opioids has been postulated to explain this observation. However, the effect of different classes of opioids on suppression of natural killer cell cytotoxicity has not been systematically characterized. METHODS: After confirming that freshly isolated natural killer cells from peripheral human blood express opioid receptors, cells were incubated with increasing concentrations of clinically used or receptor-specific opioid agonists. We also evaluated the effect of pretreatment with receptor-specific antagonists or naloxone. Treated natural killer cells were then coincubated with a carboxyfluorescein succinimidyl ester–labeled target tumor cell line, K562. Annexin V staining was used to compare the percent of tumor cell apoptosis in the presence of opioid-pretreated and untreated natural killer cells. Treated samples were compared to untreated samples using Kruskal-Wallis tests with a post hoc Dunn correction. RESULTS: Morphine, methadone, buprenorphine, loperamide, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, and U-50488 significantly decreased natural killer cell cytotoxicity. When natural killer cells were pretreated with naloxone, cyprodime, and nor-binaltorphimine before exposure to morphine, there was no difference in natural killer cytotoxicity, compared to the amount observed by untreated natural killer cells. Fentanyl, O-desmethyltramadol, and [D-Pen2,D-Pen5]enkephalin did not change natural killer cell cytotoxicity compare to untreated natural killer cells. CONCLUSIONS: Incubation of isolated natural killer cells with certain opioids causes a decrease in activity that is not overserved after naloxone pretreatment. Suppression of natural killer cell cytotoxicity was observed with μ- and κ-receptor agonists but not δ-receptor agonists. These data suggest that the effect is mediated by μ- and κ-receptor agonism and that suppression is similar with many clinically used opioids. Accepted for publication January 3, 2018. Funding: D.P.M. received funding from the Blaustein Pain Research Fund Grant and National Institutes of Health (NIH) Grant 5T32GM075774. N.M.H. receives funding from NIH Grant R01 HL124477. No copyrighted material from outside sources was used in preparation of this manuscript. This study has not been previously presented. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Dermot P. Maher, MD, MS, Johns Hopkins Blaustein Pain Treatment Center, Johns Hopkins University School of Medicine, 601 N Caroline St, Baltimore, MD 21205. Address e-mail to dmaher3@jhmi.edu. © 2019 International Anesthesia Research Society

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