Sex differences in the antinociceptive effects of the enkephalinase inhibitor, SCH 34826.

The effects of endogenous opioid peptides are limited by proteolytic enzymes such as endopeptidase 24.11 ("enkephalinase"), which cleaves the Gly-Phe bonds in Met- and Leu-enkephalin. SCH 34826 [(S)-N-[n-[1-[(2,2-dimethyl-1,3-dioxolan-4- yl)methoxy]carbonyl]-2-phenylethyl]-L-phenyl-alanine-B-alanine] is a potent, highly specific, enkephalinase inhibitor that has marked analgesic effects in laboratory rodents. The present study compared the effects of SCH 34826 on nociception and restraint stress-induced opioid analgesia in reproductive adult male and female deer mice, Peromyscus maniculatus. SCH 34826 had significantly greater antinociceptive actions and facilitatory effects on stress-induced analgesia in male than female mice. These antinociceptive effects of SCH 34826 were reduced by the general opioid antagonist naloxone and completely blocked by the specific delta opioid receptor antagonist, ICI 174,864, and nonsignificantly affected by the mu and kappa opioid receptor antagonists, beta-funaltrexamine and nor-binaltorphimine, respectively. These results show that there are sex differences in the effects of the enkephalinase inhibitor, SCH 34826, on opioid-mediated antinociception and that these sex differences are associated with delta opioid mechanisms.