2S,3R 3-amino-2-hydroxy-4-phenylbutanoic acid derivatives, enkephalinase inhibitors, augment met5-enkephalin-induced antinociception.

It has been accepted that the periaqueductal gray matter of the mid brain (PAG) and the reticular formation of the medulla oblongata in the brain stem have antinociceptive roles in the pain control pathways of mammals, and met5-enkephalin may act as one of the pain control substances in those regions. In the present study, the effects of 2S,3R 3-amino-2-hydroxy-4-phenylbutanoic acid (AHPA) derivatives on met5-enkephalin-induced antinociception were examined by a hot plate method in mice. The elevation of pain threshold induced by an intracisternal administration of met5-enkephalin was enhanced by AHPA derivatives. The rank order of potency for these agents was as follows: bestatin greater than D-Phe-AHPA greater than AHPA-D-Ala greater than p-OH-AHPA-D-Phe greater than AHPA. This order was roughly correlated to that of the enkephalinase inhibitory activity of the AHPA derivatives. These results indicate that the inhibition of enkephalinase may produce the augmentation of the exogenous met5-enkephalin-induced antinociception. It is also suggested that AHPA derivatives may cause the enhancement of the endogenous met5-enkephalin-mediated antinociception.