title: Immunosuppression by morphine-induced lymphocyte apoptosis: is it a real issue?
abstract: Morphine has been an optimal choice for cancer pain management. However, several recent studies suggested that morphine induces apoptosis in human peripheral blood lymphocytes (PBLs), raising a serious concern about the use of opioid-based analgesic strategies. In this study, therefore, we aimed to evaluate whether morphine induced apoptosis in cultured human PBLs. Apoptotic events were assessed by flow-cytometrical detection of surface phosphatidylserine and nuclear fragmentation, as well as Fas, Bcl-2, and Caspase-3 activity in PBLs gated on a light-scatter basis. Peripheral blood mononuclear cells isolated from healthy subjects were cultured with etoposide, morphine, or vehicle (medium) for 48 h. During co-culture with etoposide, apo-ptosis was significantly induced in PBLs, and the cells did not survive for 48 h. In comparison, morphine had no effect on the expression rate of any of the detected molecules, suggesting that no apparent apoptotic processes were induced during the incubation. Furthermore, co-incubation with a Fas-specific antibody did not increase apoptotic cell rates in the morphine cultures. These results do not support the hypothesis that morphine directly modulates PBL apoptosis resulting in immunosuppression. We believe that the choice of opioids for optimal pain relief should not be discouraged until further studies clarify this issue.
  
  
  CONCLUSIONS
  Recent reports that morphine potentially induces apoptosis in human lymphocytes in vitro have raised a concern about the use of opioid-based analgesic strategies. Regarding this issue, we present rather contradictory findings that morphine has no effects on the cell expression of various apoptosis-related molecules in cultured human lymphocytes.
authors.affiliation: *Division of Pain Control, Department of Anesthesiology and Emergency Medicine, and †Division of Immunology and Embryology, Department of Cell Biology, Tohoku University Graduate School of Medicine, and ‡Division of Dento-oral Anesthesiology, Department of Oral Medicine and Surgery, Tohoku University Graduate School of Dentistry, Sendai, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ohara
authors.forename: Tsunetoshi
authors.initials: T
authors.lastname: Itoh
authors.forename: Masahiko
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D017304:Annexin A5 / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003609:Dactinomycin / Q000031:analogs & derivatives / Q000032:analysis; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D009020:Morphine / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D019014:fas Receptor / Q000032:analysis
chemical_list: D017304:Annexin A5; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D003609:Dactinomycin; C025942:7-aminoactinomycin D; D009020:Morphine