Peripherally active analgesia of aminopeptidase-resistant sugar-coupled leucine enkephalin

Aminopeptidase-degradable leucine enkephalin (LE) was coupled with disaccharide (cellobiose or gentiobiose). Acetic acid writhing assay (for peripheral effect) showed that cellobiose-coupled LE (CcpLE) as well as LE had analgesic activity by subcutaneous (s.c.) administration to mice pretreated (s.c. administration) with peptidase inhibitors, whereas any analgesic effect was not observed after s.c. administration of CcpLE or LE without peptidase inhibitors. However, gentiobiose-coupled LE (EcpLE) did not have analgesic activity even with pretreatment of peptidase inhibitors. On the other hand, hot-plate assay (for central effect) did not indicate obvious analgesic effect after s.c. administration of CcpLE or EcpLE with pretreatment of peptidase inhibitors. Significant difference of stability against peptidase was not observed between CcpLE and EcpLE. Therefore, it was concluded that CcpLE is a peripherally active analgesic.