The role of LGL/NK cells in surgery-induced promotion of metastasis and its attenuation by morphine

Brain Behav Immun. 1994 Sep;8(3):241-50. doi: 10.1006/brbi.1994.1022.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / secondary
  • Animals
  • Cell Adhesion
  • Cytotoxicity, Immunologic
  • Immune Tolerance*
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Laparotomy / adverse effects*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / secondary
  • Lymphocyte Count / drug effects
  • Lymphocyte Depletion
  • Lymphocyte Subsets / drug effects
  • Lymphocyte Subsets / immunology*
  • Male
  • Mammary Neoplasms, Experimental / immunology
  • Mammary Neoplasms, Experimental / pathology
  • Morphine / pharmacology*
  • Neoplasm Metastasis / immunology*
  • Neoplasm Transplantation
  • Neuroimmunomodulation
  • Pain, Postoperative / drug therapy
  • Pain, Postoperative / immunology*
  • Random Allocation
  • Rats
  • Rats, Inbred F344
  • Stress, Physiological / etiology
  • Stress, Physiological / immunology*


  • Morphine