1998 Fiscal Year Final Research Report Summary
Molecular Biological Study of the Signal Transduction Mechanism of the G-Protein-Coupled Receptors Involved in Pain
| Project/Area Number |
09307035
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (A)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Anesthesiology/Resuscitation studies
|
|---|
| Research Institution | KYOTO UNIVERSITY |
|---|
Principal Investigator |
FUKUDA Kazuhiko Kyoto University Faculty of Medicine, Department of Anesthesia, Professor, 医学研究科, 教授 (90199224)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MORI Kenjiro Kyoto University Faculty of Medicine, Department of Anesthesia, Professor Emerit, 医学研究科, 名誉教授 (20025620)
|
|---|
| Project Period (FY) |
1997 – 1998
|
| Keywords | Nociceptin / Opioid / Mitogen-activated protein kinase / Phospholipase A_2 / Ca^<2+> channel / Desensitization / Down-regulation |
|---|
| Research Abstract |
In this investigation, we analyzed signal transduction mechanism and adaptation mechanism to chronic agonist exposure of the nociceptin receptor and the opioid receptor, using molecular biological, biochemical and electrophysiological methods.
Activation of the nociceptin receptor expressed by transfection of the cloned cDNA in CHO cells induced activation of mitogen-activated protein kinase (MAPK) and phosphorylation of phospholipase A_2, leading to arachidonate release in the presence of a calcium ionophore A23187. Furthermore, stimulation of the nociceptin receptor endogenously expressed in NG108-15 cells induced inhibition of the N-type Ca^<2+> channel.
Agonist stimulation of the mu-opioid receptor expressed in CHO cells induced internalization of the receptor followed by down-regulation, supersensitization of adenylate cyclase and slight desensitization of the mu-opioid receptor. These cellular adaptation responses to chronic agonist exposure may be involved in tolerance and dependence to opioid analgesics, that are serious problems in clinical settings. Chronic agonist exposure of the delta-opioid receptor endogenously expressed in NG108-15 cells was demonstrated to cause desensitization of the opioid-induced inhibition of the N-type Ca^<2+> channel activity. We found that beta-adrenergic receptor kinase is involved in the desensitization mechanism.
Naloxone has been so far thought as a pure antagonist of the mu-, delta- and kappa-opioid receptors. However, by analyzing pharmacological effects of naloxone on the opioid receptors expressed heterologously in CHO cells, we found that naloxone has partial agonistic activity on the mu- and kappa-opioid receptors.
|
-
-
-
-
-
-
-
-
-
-
-
-
[Publications] Mima, H., Morikawa, H., Fukuda, K., Kato, S., Shoda, T.and Mori, K.: "Ca^<2+> channel inhibition by indomorphins via the mu-opioid receptor expressed in NG108-15 cells." Eur.J.Pharmacol.340. R1-R2 (1997)
Description
「研究成果報告書概要(欧文)」より
-
[Publications] Kato, S., Fukuda, K., Morikawa, H., Shoda, T., Mima, H.and Mori, K.: "Adaptations to chronic agonist exposure of mu-opioid receptor-expressing Chinese hamster overy cells." Eur.J.Pharmacol.345. 221-228 (1998)
Description
「研究成果報告書概要(欧文)」より
-
[Publications] Morikawa, H., Fukuda, K., Mima, H., Shoda, T., Kato, S.and Mori, K.: "Desensitization and resensitization of delta-opioid receptor-mediated Ca^<2+> channel inhibition in NG108-15 cells." Brit.J.Pharmacol.123. 1111-1118 (1998)
Description
「研究成果報告書概要(欧文)」より
-
[Publications] Morikawa, H., Fukuda, K., Mima, H., Shoda, T., Kato, S.and Mori, K.: "Nociceptin receptor-mediated Ca^<2+> channel inhibition and its desensitization in NG108-15 cells." Eur.J.Pharmacol.351. 247-252 (1998)
Description
「研究成果報告書概要(欧文)」より
-
[Publications] Morikawa, H., Fukuda, K., Mima, H., Shoda, T., Kato, S.and Mori, K.: "Tyrosine kinase inhibitors suppress N-type and T-type Ca^<2+> channel currents in NG108-15 cells." Pflugers Arch.Eur.J.Physiol. 436. 127-132 (1998)
Description
「研究成果報告書概要(欧文)」より
-
[Publications] Fukuda, K., Kato, S., Shoda, T., Morikawa, H., Mima, H.and Mori, K.: "Partial agonistic activity of naloxone on the receptors expressed in Chinese hamster ovary cells." Anesth.Analg.87. 450-455 (1998)
Description
「研究成果報告書概要(欧文)」より
-
[Publications] Fukuda, K., Shoda, T., Morikawa, H., Kato, S., Mima, H.and Mori, K.: "Activation of phospholipase A_2 by the nociceptin receptor expressed in Chinese hamster ovary cells." J.Neurochem. 71. 2186-2192 (1998)
Description
「研究成果報告書概要(欧文)」より
-
[Publications] Furukawa, T., Nukada, T., Mori, Y., Wakamori, M., Fujita, Y., Ishida, H., Fukuda, K., Kato, S.and Yoshii, M.: "Differential interactions of the C terminus and the cytoplasmic I-II loop of neuronal Ca^<2+> channels with G-protein alpha and betagamma subunits. I.Molecular determination." J.Biol.Chem.273. 17585-17594 (1998)
Description
「研究成果報告書概要(欧文)」より
-
[Publications] Shoda, T., Fukuda, K., Kato, S., Morikawa, H., Mima, H.and Mori, K.: "Adaptive Cellular Responses Induced by Chronic Agonist Treatment of the Nociceptin Receptor-Expressing Chinese Hamster Ovary Cells." New Balanced Anesthesia (Mori, K., Ohmura, A., Toyooka, H., Hatano, Y., Shingu, K.and Fukuda, K., eds). Excerpta Medica, Amsterdam. 323-324 (1998)
Description
「研究成果報告書概要(欧文)」より
