Intracerebroventricular administration of
phelorphan (158 nmol/2 microliters), a blocker of dipeptidylaminopeptidase (
enkephalinase B) and other
enzymes involved in the
enkephalin biodegradation, inhibited in chronic
morphine-dependent rats, the occurrence of some of the
naloxone-precipitated
withdrawal symptoms. This effect of
phelorphan was compared with an equimolar dose of the
dipeptidyl-carboxypeptidase inhibitor (
enkephalinase A),
thiorphan. The results indicate that both drugs decrease some of the
naloxone-precipitated
withdrawal symptoms (writhing, digging, head hiding, chewing, diarrhoea and Straub tail), while others were potentiated (penile licking) or unaltered (wet dog shakes, grooming and rearing). In addition,
phelorphan compared with the controls or
thiorphan, pretreated animals, increased the frequency of paw
tremor, head shakes, scratching, erection and ejaculation, but other symptoms were decreased (stretching) or unaltered (teeth chattering). The results are discussed in light of the differences in permeability and specificity of the two
enkephalinase inhibitors. Furthermore, these data support the hypothesis that the use of
enkephalinase inhibitors might be a promising way for the attenuation of the severity of the withdrawal syndrome.