title: Effects of fentanyl on natural killer cell activity and on resistance to tumor metastasis in rats. Dose and timing study.
abstract: OBJECTIVE
  Opiates, which serve an integral role in anesthesia, suppress immune function, particularly natural killer cell cytotoxicity (NKCC). NK cells play an important role in tumor and metastasis surveillance. We reported that large-dose fentanyl anesthesia induced prolonged suppression of NKCC in patients undergoing abdominal surgery. The immune modulatory effects of opiates may depend on the interaction between dose and time of administration. The present study examined the effects of different doses of fentanyl, administered at different time points relative to tumor inoculation, on NKCC and on experimental tumor metastasis in rats.
  
  
  METHODS
  Fischer 344 rats were injected with low or high doses of fentanyl, 6 or 2 h before, simultaneously with or 1 h after being inoculated intravenously with MADB106 tumor cells. Lung tumor retention (LTR) was assessed 4 h after, and lung tumor metastases were counted 3 weeks after tumor inoculation. NKCC was assessed 1 h after the fentanyl injection.
  
  
  RESULTS
  At all time points, except 6 h before tumor inoculation, fentanyl (0.1-0.3 mg/kg) induced a dose-dependent increase in MADB106 LTR (2.3- to 74-fold). An intermediate dose of fentanyl (0.15 mg/kg) doubled the number of lung metastasis, and, within animal, suppressed NKCC and increased MADB106 LTR in a correlated manner.
  
  
  CONCLUSIONS
  These findings indicate that fentanyl suppresses NKCC and increases the risk of tumor metastasis. Suppression of NK cells at a time when surgery may induce tumor dissemination can prove to be critical to the spread of metastases. It is suggested that the acute administration of a moderate dose of opiates during surgery should be applied cautiously, particularly in cancer patients.
authors.affiliation: Department of Psychology, Hebrew University, Jerusalem, Israel. Udi.Shavit@huji.ac.il
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Shavit
authors.forename: Shamgar
authors.initials: S
authors.lastname: Ben-Eliyahu
authors.forename: Alexander
authors.initials: A
authors.lastname: Zeidel
authors.forename: Benzion
authors.initials: B
authors.lastname: Beilin
mesh_terms: D000230:Adenocarcinoma / Q000556:secondary*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005283:Fentanyl / Q000494:pharmacology*; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary*; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000276:immunology* / Q000503:physiopathology; D009368:Neoplasm Transplantation; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000701:Analgesics, Opioid; D007166:Immunosuppressive Agents; D005283:Fentanyl