title: The role of LGL/NK cells in surgery-induced promotion of metastasis and its attenuation by morphine.
abstract: Painful stress such as surgery has been shown both to suppress immune function and to promote metastasis, although the degree to which alterations in immunity underlies the tumor-enhancing effects of surgery remains unclear. We recently reported that an experimental laparotomy results in a twofold increase in the number of lung metastases following iv injection of MADB106 tumor cells, a natural killer (NK)-sensitive mammary adenocarcinoma cell line, syngeneic to the Fischer 344 rats we studied. Further, the administration of an analgesic dose of morphine prevented these metastatic-enhancing effects of surgery. The aim of the present study was to investigate the role of NK cells in both the metastatic-enhancing effects of surgery and the attenuation of these effects by morphine. Using a simple 2 x 2 experimental design (surgery with anesthesia vs anesthesia only, and morphine vs vehicle), we found that surgery resulted in a decrease in both whole blood NK cytotoxic activity and number of circulating LGL/NK cells assessed 4 h postoperatively. In a second experiment involving an 18-h lung clearance assay, we used the mAb 3.2.3 to deplete rats of LGL/NK cells with the following rationale: if LGL/NK cells are necessary to mediate an event, then in their absence, that event should not occur. Normal and LGL/NK-depleted animals were assigned to the same four experimental groups, and radiolabeled MADB106 tumor cells were injected iv 4 h after surgery. In normal animals, there was a significant interaction between surgery and morphine such that morphine attenuated the surgery-induced increase in tumor cell retention without affecting tumor cell retention in the anesthesia groups. In the LGL/NK-depleted animals, however, although the tumor-enhancing effects of surgery remained evident, morphine did not mitigate this outcome. These results suggest that: (a) both LGL/NK cell activity and other factors independent of LGL/NK cells play a role in the surgery-induced increase in tumor cell retention; and (b) LGL/NK cells play a critical role in morphine's attenuating effects on this outcome. Finally, these results reinforce concern about the pathogenic consequences of unrelieved pain.
authors.affiliation: College of Nursing, Ohio State University, Columbus 43210.
authors.forename: G G
authors.initials: GG
authors.lastname: Page
authors.forename: S
authors.initials: S
authors.lastname: Ben-Eliyahu
authors.forename: J C
authors.initials: JC
authors.lastname: Liebeskind
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000556:secondary; D000818:Animals; D002448:Cell Adhesion; D003602:Cytotoxicity, Immunologic; D007108:Immune Tolerance; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D007813:Laparotomy / Q000009:adverse effects*; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary; D018655:Lymphocyte Count / Q000187:drug effects; D008212:Lymphocyte Depletion; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D009020:Morphine / Q000494:pharmacology*; D009362:Neoplasm Metastasis / Q000276:immunology*; D009368:Neoplasm Transplantation; D015213:Neuroimmunomodulation; D010149:Postoperative Pain / Q000188:drug therapy / Q000276:immunology*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D013312:Stress, Physiological / Q000209:etiology / Q000276:immunology*
chemical_list: D009020:Morphine