Attempt of obstinacy pain easing by spinal cord GABA-B receptor continuation activation.
| Project/Area Number |
17500254
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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 |
Neurochemistry/Neuropharmacology
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| Research Institution | Nagasaki University |
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Principal Investigator |
UEZONO Yasuhito Nagasaki University, Graduate School of Biomedical Sciences, Associate Professor, 大学院医歯薬学総合研究科, 助教授 (20213340)
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| Co-Investigator(Kenkyū-buntansha) |
MINAMI Kohichiro University of Occupational and Environmental Health, Lecturer, 医学部, 講師 (70279347)
TANIYAMA Kohtaro Nagasaki University, Graduate School of Biomedical Sciences, Professor, 大学院医歯薬学総合研究科, 教授 (70030898)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | Desensitization of GABA_B receptors / GRK4 / Ketamine / FRET / Immunochemistry / Persistent analgesia / 持続的鎮痛緩和 / 接続的鎮痛緩和 |
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| Research Abstract |
Recent reports have shown that intrathecal administration of GABA_B receptor agonist baclofen (ITB, intrathecal baclofen) is effective for intolerable pain such as neuropathic pain. Even such effective ITB therapy, prolonged application of baclofen causes tolerance and then decreases analgesic effects in patients. The main cause of the tolerance of ITB therapy arises from desensitization of GABA_B receptors due to continuous activation of the receptors. We have recently reported that G protein-coupled receptor kinase 4 (GRK4) and GRK5 are involved in the desensitization processes of GABA_B receptors (Kanaide et al., J Cell Physiol. (2007)). In the present study we sought to find drugs that inhibit GRK4 and GRK5 activity to persistently stimulate GABA_B receptors.
Our findings suggest that ketamine, an anesthetic and an inhibitor of NMDA receptors, efficiently inhibited the properties of GRK4 and GRK5 to finally cause attenuation of desensitization of GABA_B receptors induced by prolonged application of baclefen in the Xenopus oocyte and baby hamster kidney cell expression systems.
These results imply that co-administration of both baclofen and ketamine may inhibit desensitization of GABA_B receptors and eventually cause persistent analgesic effects without tolerance in the ITB therapy. Further studies with the whole body animals and preliminary clinical trials would be required to confirm the 'safe and effective ITB therapy' for patients suffering from severe pain.
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Report
(3 results)
Research Products
(39 results)
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[Journal Article] Desensitization of GABA_B receptor signaling by formation of protein complexes of GABA_<B2> subunit with GRK4 or GRK5.2007
Author(s)
KANAIDE, M., UEZONO, Y., MATSUMOTO, M., HOJO, M., ANDO, Y., SUDO, Y., SUMIKAWA, K., TANIYAMA, K.
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Journal Title
Journal of Cellular Physiology 210
Pages: 237-245
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Coupling of the GABA_B receptor GABA_<B2> subunit to G protein : Evidence from the Xenopus oocyte and baby hamster kidney cell expression system.2006
Author(s)
UEZONO, Y., KANAIDE, M., KAIBARA, M., BARZILAI, L., DASCAL, N., SUMIKAWA, K., TANIYAMA, K.
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Journal Title
American Journal of Physiology-Cell Physiology 269
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The Tramadol Metabolite O-desmethyl tramadol inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes.2006
Author(s)
HORISHITA, T., MINAMI, K., UEZONO, Y., SHIRAISHI, M., OGATA, J., OKAMOTO, T., SATA, T., SHIGEMATSU, A.
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Journal Title
Pharmacology 77
Pages: 93-99
Description
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[Journal Article] Selective blockade of nicotinic acetylcholine receptors by pimobendan, a drug for the treatment of heart failure : reduction of catecholamine secretion and synthesis in adrenal medullary cells.2005
Author(s)
TOYOHIRA, Y., KUBO, T., WATANABE, M., UEZONO, Y., YANAGIHARA, N., IZUMI, F.
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Journal Title
Naunyn-Schmiedeberg's Archives of Pharmacology 371
Pages: 107-113
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] The effects of the tramadol metabolite o-desmethyl tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned m1 or m3 receptors.2005
Author(s)
NAKAMURA, M., MINAMI, K., UEZONO, Y., HORISHITA, T., OGATA, J., SHIRAISHI, M., OKAMOTO, T., TERADA, T., SATA, T.
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Journal Title
Anesthesia and Analgesia 101
Pages: 180-186
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The effects of neurosteroids : pregnenoron, dehydroepiandrosterone, progesterone on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M1 and M3 receptors.2005
Author(s)
HORISHITA, T., MINAMI, K., UEZONO, Y.OGATA, J., SHIRAISHI, M., OKAMOTO, T., TERADA, T., SATA, T.
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Journal Title
Naunyn Schmiedeberg's Archives of Pharmacology 371
Pages: 221-228
Description
「研究成果報告書概要(欧文)」より
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