We have previously shown that the pre- and postoperative administration of an analgesic dose of morphine attenuated the tumour-enhancing effects of surgery. This study was undertaken to assess the relative role and exclusive importance of pre- versus postoperative morphine administration on neuroendocrine, metastatic, and behavioural outcomes of surgery in Fischer 344 rats. The natural killer (NK) sensitive mammary adenocarcinoma cell line, MADB106, was used in a lung clearance assay to assess host resistance to metastasis. Either morphine or its vehicle was administered to all rats at three times: (1) 30 min before surgery (8 mg kg-1, in saline); (2) immediately after surgery in a slow release 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 groups underwent an experimental laparotomy with halothane anaesthesia and received either the vehicle at all three times or morphine in one of four different regimens: before surgery only, at all three times, after 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 underwent 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 morphine treatment regimens (P < 0.05). Furthermore, the two surgery groups that 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, only a 50% attenuation was evident in the two groups treated postoperatively. Surgery significantly reduced rearing behaviour and morphine reversed this effect such that most morphine-treated surgery groups exhibited similar levels of rearing behaviour as was observed in the unoperated animals throughout the 4-h postoperative observation period. Morphine 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 suggestion that the pre-surgical administration of morphine is key in optimizing its beneficial effects on surgery-induced increases in metastasis.