Comparison of selective and complete inhibitors of enkephalin-degrading enzymes on morphine withdrawal syndrome.

We investigated the effects of thiorphan, a selective inhibitor of endopeptidase 24.11 'enkephalinase', kelatorphan ((R)-3-(N-hydroxy-carboxamido-2-benzylpropanoyl)-L-alanine), and RB 38 A ((R)-3-(N-hydroxycarboxamido-2-benzylpropanoyl)-L-phenylalanine) two almost complete inhibitors of enkephalin metabolism, on the naloxone-precipitated morphine withdrawal syndrome in rats. Inhibitors administered intracerebroventricularly reduced several symptoms of the withdrawal syndrome. Jumping, chewing and tooth chattering were decreased by all drugs. The rise in plasma corticosterone and the hypothermia were reduced by kelatorphan and RB 38 A whereas rhinorrhea was blocked by thiorphan, tremor by kelatorphan and diarrhoea by RB 38 A. Other signs remained unchanged. These data suggest that an increase in opioid receptor occupancy by endogenous opioid peptides, protected from biotransformation specially by mixed inhibitors reduced the severity of the morphine abstinence symptoms in rats.