RB 101, A PURPORTED PRO DRUG INHIBITOR OF ENKEPHALIN METABOLISM, IS ANTINOCICEPTIVE IN PREGNANT MICE

In an earlier study, we demonstrated the enhancement of pregnancy-indu ced analgesia with an inhibitor of endogenous enkephalin metabolism. T he purpose of the present study was to evaluate the antinociceptive ef fect of another inhibitor of enkephalin metabolism, RE 101, on pregnan t mice. Further, since other studies have shown RE 101 to be free of o pioid side effects, we examined its effect on respiratory rate. Analge sia was assessed using the hot plate test, and respiratory rate was me asured by recording the output from an end-tidal carbon dioxide detect or. In pregnant mice, experiments were conducted on Day 17 or Day 18 o f pregnancy; mice usually deliver on Day 19. For the hotplate test, an imals were tested in the following groups: Group 1, RE 101 150 mg/kg ( n = 15); Group 2, RE 101 50 mg/kg (n = 15); Group 3, RE 101 vehicle (n = 15); Group 4, morphine 5 mg/kg (n = 14); and Group 5, RE 101 150 mg /kg + naloxone 5 mg/kg (n = 10). The test was repeated on the second d ay after delivery in animals in Groups 1 and 3 (given RE 101 150 mg/kg and RE 101 vehicle, respectively). RE 101 150 mg/kg and morphine 5 mg /kg were significantly different (mean percentage of maximum possible effect 30.0 and 37.7, respectively, at 30 min and 41.6 and 32.6, respe ctively, at 60 min) in their antinociceptive effect in pregnant animal s from all other groups. Naloxone, when coadministered with RE 101, pr evented the development of antinociception. RE 101 150 mg/kg was not a ntinociceptive after delivery. Depression of respiratory rate was test ed in a separate set of animals in the following groups: Group 1, RE 1 01 150 mg/kg (n = 16); Group 2, morphine 5 mg/kg (n = 16); Group 3, RE 101 vehicle (n = 15). Morphine 5 mg/kg produced significant depressio n of respiratory rate at 30 min postinjection when compared with RE 10 1 150 mg/kg and RE 101 vehicle (mean percent change in respiratory rat e was 78.5% compared with 87.7% and 92.4%, respectively, where 100% = no change). These results suggest that drugs such as RE 101 may produc e antinociception with minimal effects on respiration.