Degradation of endomorphin-2 at the supraspinal level in mice is initiated by dipeptidyl peptidase IV: anin vitroandin vivostudy

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Endomorphin-2 (Tyr-Pro-Phe-PheNH2) was discovered as an endogenous ligand for the μ-opioid receptor. The physiological function of endomorphin-2 as a neurotransmitter or neuromodulator may cease through the rapid enzymatic process in the synapse of brain, as for other neuropeptides. The present study was conducted to examine the metabolism of endomorphin-2 by synaptic membranes prepared from mouse brain. Major metabolites were free tyrosine, free phenylalanine, Tyr-Pro and PheNH2. Both the degradation of endomorphin-2 and the accumulation of major metabolites were inhibited by specific inhibitors of dipeptidyl peptidase IV, such as diprotin A and B. On the other hand, the accumulation of Phe-PheNH2 and Pro-Phe-PheNH2 was increased in the presence of bestatin, an aminopeptidase inhibitor, whereas that of free phenylalanine and PheNH2 was decreased. Furthermore, purified dipeptidyl peptidase IV hydrolyzed endomorphin-2 at the cleavage site, Pro2-Phe3 bond. Thus, degradation of endomorphin-2 by brain synaptic membranes seems to take place mainly through the cleavage of Pro2-Phe3 bond by dipeptidyl peptidase IV, followed by release of free phenylalanine and PheNH2 from the liberated fragment, Phe-PheNH2 by aminopeptidase. We have also examined that the effect of diprotin A on the antinociception induced by intracerebroventricularly administered endomorphin-2 in the mouse paw withdrawal test. Diprotin A simultaneously injected with endomorphin-2 enhanced endomorphin-2-induced antinociception. These results indicate that dipeptidyl peptidase IV may be an important peptidase responsible for terminating endomorphin-2-induced antinociception at the supraspinal level in mice.

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