AN ENKEPHALINASE INHIBITOR, SCH-32615, AUGMENTS ANALGESIA INDUCED BY SURGERY IN MICE

Background: Stress-induced analgesia is a well recognized phenomenon i n animals and humans in which endogenous opioids have been implicated. However, analgesia induced by surgical stress has not been reported. The purpose of this study was to determine whether surgery evokes anal gesia and to examine the effect of SCH 32615, an inhibitor of one of t he enzymes (enkephalinase) responsible for the degradation of enkephal ins, on this analgesia, in mice. Methods: Analgesia was tested using t he hot-plate test. Animals were tested before any procedure was done a nd then at hourly intervals thereafter. Under halothane anesthesia, th e anterior abdominal wall was incised, and the abdominal aorta was com pressed against the vertebral column for 1 s. This was repeated for a total of three times at 5-s intervals. At the end of the procedure, th e following drug(s) were administered subcutaneously to different grou ps of animals: (1) no drugs, only surgery (n = 15); (2) 5 mg/kg naloxo ne (n = 15); (3) 150 mg/kg SCH 32615 (n = 14); (4) 150 mg/kg SCH 32615 plus 5 mg/kg naloxone (n = 15); and (5) SCH 32615 vehicle (0.9% methy lcellulose; n = 13). Two more groups of animals were included as contr ols and were anesthetized, but no surgical procedure was performed, On e control group (n = 13) received 0.9% methylcellulose and the other 1 50 mg/kg SCH 32615 (n = 12). Results: Hot-plate latency was significan tly longer after surgery (hot-plate latency at 4 h after surgery 29.3 +/- 3.2 (SE) s and at 5 h 30.7 +/- 5 s versus baseline 15.8 +/- 7 s; P < 0.05). Naloxone (5 mg/kg) inhibited this analgesic effect of surger y. SCH 32615 significantly enhanced this analgesia (percentage of maxi mal possible effect (%MPE) at 4 h 33.7 +/- 8.7%, at 5 h 27.5 +/- 4.7%, and at 6 h 23.2 +/- 4.7%; P < 0.05 compared to all other groups), and naloxone antagonized its effect. Anesthesia without surgery did not e voke subsequent analgesia, and SCH 32615 was not analgesic in the abse nce of antecedent surgery. Conclusions: Surgery activated endogenous a nalgesia, the development of which was prevented by naloxone. SCH 3261 5, an enkephalinase inhibitor, significantly enhanced this analgesia.