1996 Fiscal Year Final Research Report Summary
Molecular Basis of Opioid Receptor Function and Molecular Mechanism for Opioid Tolerance
| Project/Area Number |
06404056
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Anesthesiology/Resuscitation studies
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
MORI Kenjiro Kyoto University, Faculty of Medicine, Department of Anesthesia, Professor, 医学研究科, 教授 (20025620)
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| Co-Investigator(Kenkyū-buntansha) |
FUKUDA Kazuhiko Kyoto University, Faculty of Medicine, Department of Anesthesia, Assistant Profe, 医学研究科, 講師 (90199224)
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| Project Period (FY) |
1994 – 1996
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| Keywords | Opioid receptor / Ligand selectivity / Ca^<2+> channel / MAP kinase / Phospholipase A2 / Tolerance / Cyclic AMP |
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| Research Abstract |
The opioid receptor is pharmacologically classified into mu, delta and kappa on the basis of the difference in ligand binding affinity. To elucidate which portion of the opioid receptor molecule determines the difference in ligand binding affinity, we constructed chimeric receptors between the mu-and delta-opioid receptors, and analyzed their ligand binding properties. The results obtained suggest that the difference in binding affinity for DAGO,a mu-selective agonist, is determined by the difference in amino acid sequence of the region spanning the transmembrane segments II-III.Furthermore, analysis of the mutant receptors, in which one amino acid residue in the region spanning the transmembrane segments II-III is substututed, suggest that one amino acid difference between the mu-and delta-receptors determines the difference in DAGO binding affinity.
We transfected NG108-15 cells with the mu-opioid receptor cDNA and analyzed agonist-induced response of Ca^<2+> channels by the patch cla
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mp method. The results obtained indicate that activation of the mu-receptor leads to inhibition of the N-type Ca^<2+> channels through the action of pertussis toxin-sensitive G-proteins.
We expressed opioid receptors in chinese hamster ovary (CHO) cells by cDNA transfection, and analyzed opioid agonist-induced change in MAP kinase activity. Our results indicate that activation of the opioid receptors induces activation of MAP kinase, and that pertussis toxin-sensitive G-proteins and protein kinase C are involved in this response. Furthermore, we dumonstrated that opioid-induced MAP kinase activation results in activation of phospholipase A2 and arachidonic acid release.
Using CHO cells stably transfected with the mu-opioid receptor cDNA,changes in opioid receptor fuction induced by chronic agonist stimulation were analyzed. Chronic agonist stimulation induced internalization and down-regulation of the mu-receptor, and increase in cyclic AMP production by adenylate cyclase.
These results described above can be expected to contribute to understanding of the molecular basis of the opioid receptor function and elucidation of the molecular mechanism for opioid tolerance. Less
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[Publications] Fukuda, K., Kato, S., Morikawa, H., Shoda, T. and Mori, K.: "Functional coupling of the δ-, μ-, and κ-opioid receptors to mitogen-activated protein kinase and arachidonate release in Chinese hamster ovary cells." Journal of Neurochemistry. 67. 1306-1316 (1996)
Description
「研究成果報告書概要(和文)」より
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[Publications] Fukuda, K., Kato, S., Morikawa, H., Shoda, T.and Mori, K.: "Functional coupling of the delta-, mu-, and kappa- opioid receptors to mitogen-activated protein kinase and arachidonate release in Chinese hamster ovary cells." J.Neurochem. 67. 1306-1316 (1996)
Description
「研究成果報告書概要(欧文)」より
