2004 Fiscal Year Final Research Report Summary
Development of a New Analgesic Based on Metabolism of Endomorphin, an Endogenous Opioid Peptide
| Project/Area Number |
15590086
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Nihon Pharmaceutical University (2004)
Daiichi University, College of Pharmaceutical Sciences (2003) |
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Principal Investigator |
SAKURADA Chikai Nihon Pharmaceutical University, Department of Biochemistry, Associate Professor, 薬学部, 助教授 (30279244)
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| Co-Investigator(Kenkyū-buntansha) |
SAKURADA Tsukasa Daiichi College of Pharmaceutical Sciences, Department of Biochemistry, Professor, 薬学部, 教授 (80124907)
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| Project Period (FY) |
2003 – 2004
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| Keywords | antinociception / dipeptidyl peptidase IV / endomorphin-2 / metabolic pathway / mouse brain / synaptic membranes |
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| Research Abstract |
Endomorphin-2 (Tyr-Pro-Phe-PheNH_2) was discovered as an endogenous ligand for the mu-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 PheNH_2. 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-PheNH_2 and Pro-Phe-PheNH_2 was increased in the presence of bestatin, an aminopeptidase inhibitor, whereas that of free phenylalanine and PheNH_2 was decreased. Furthermore, purified dipeptidyl peptidase IV hydrolyzed endomorphin-2 at the cleavage site, Pro^2-Phe^3 bond. Thus, degradation of endomorphin-2 by brain synaptic membranes seems to take place mainly through the cleavage of Pro^2-Phe^3 bond by dipeptidyl peptidase IV, followed by release of free phenylalanine and Phe NH_2 from the liberated fragment, Phe-Phe NH_2 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. These findings also suggest that selective dipeptidyl peptidase IV inhibitors or dipeptidyl peptidaseIV-resistant endomorphin-2 analogues have the potential for the clinical use as analgesics.
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