A series of new methionine-enkephalin analogs containing trifluoronorvaline (TFNV) or trifluoronorleucine (TFNL) in place of Gly² or Gly³ are synthesized. The new analogs bearing (D)-TFNV in place of Gly² exhibit ca. 100,000 times enhancement in in vivo analgesic activity in comparison with methionine-enkephalin. The in vitro binding assays for mu, delta and kappa receptors reveal that this enhancement is not based on the much stronger binding to these receptors, but mainly due to the extremely efficient inhibition of degradation by aminopeptidase(s).