An enkephalinase inhibitor, SCH 32615, augments analgesia induced by surgery in mice

Background: Stress-induced analgesia is a well recognized phenomenon in 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 analgesia and to examine the effect of SCH 32615, an inhibitor of one of the enzymes (enkephalinase) responsible for the degradation of enkephalins, on this analgesia, in mice.

Methods: Analgesia was tested using the hot-plate test. Animals were tested before any procedure was done and then at hourly intervals thereafter. Under halothane anesthesia, the anterior abdominal wall was incised, and the abdominal aorta was compressed 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, the following drug(s) were administered subcutaneously to different groups of animals: (1) no drugs, only surgery (n = 15); (2) 5 mg/kg naloxone (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% methylcellulose; n = 13). Two more groups of Animals were included as controls and were anesthetized, but no surgical procedure was performed. One control group (n = 13) received 0.9% methylcellulose and the other 150 mg/kg SCH 32615 (n = 12).

Results: Hot-plate latency was significantly 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 surgery. SCH 32615 significantly enhanced this analgesia (percentage of maximal 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 evoke subsequent analgesia, and SCH 32615 was not analgesic in the absence of antecedent surgery.

Conclusions: Surgery activated endogenous analgesia, the development of which was prevented by naloxone. SCH 32615, an enkephalinase inhibitor, significantly enhanced this analgesia.