PREOPERATIVE VERSUS POSTOPERATIVE ADMINISTRATION OF MORPHINE - IMPACTON THE NEUROENDOCRINE, BEHAVIORAL, AND METASTATIC-ENHANCING EFFECTS OF SURGERY

We have previously shown that the pre- and postoperative administratio n of an analgesic dose of morphine attenuated the tumour-enhancing eff ects of surgery. This study was undertaken to assess the relative role and exclusive importance of pre- versus postoperative morphine admini stration on neuroendocrine, metastatic, and behavioural outcomes of su rgery in Fischer 344 rats. The natural killer (NK) sensitive mammary a denocarcinoma cell line, MADB106, was used in a lung clearance assay t o assess host resistance to metastasis. Either morphine or its vehicle was administered to all rats at three times: (1) 30 min before surger y (8 mg kg(-1), in saline); (2) immediately after surgery in a slow re lease suspension (SRS, 4 mg kg(-1)); and (3) 5 h after surgery at the time of tumour cell inoculation (2 mg kg(-1), in SRS). Five surgery gr oups underwent an experimental laparotomy with halothane anaesthesia a nd received either the vehicle at all three times or morphine in one o f four different regimens: before surgery only, at all three times, af ter surgery only at times 2 and 3, and after surgery total at times 2 and 3 with the preoperative dose added at time 2. Two control groups u nderwent anaesthesia alone and received either morphine or the vehicle at all three times. Surgery resulted in a twofold increase in tumour cell retention, which was significantly attenuated by all four morphin e treatment regimens (P<0.05). Furthermore, the two surgery groups tha t were treated with morphine preoperatively appeared to derive greater benefit; whereas the preoperatively treated groups exhibited a 65-70% attenuation of surgery-induced increases in tumour cell retention, on ly a 50% attenuation was evident in the two groups treated postoperati vely. Surgery significantly reduced rearing behaviour and morphine rev ersed this effect such that most morphine-treated surgery groups exhib ited similar levels of rearing behaviour as was observed in the unoper ated animals throughout the 4-h postoperative observation period. Morp hine treatment also significantly attenuated surgery-induced increases in plasma corticosterone concentrations assessed at 5 h after surgery . If such relationships hold in humans, these findings support the sug gestion that the pre-surgical administration of morphine is key in opt imizing its beneficial effects on surgery-induced increases in metasta sis.