2000 Fiscal Year Final Research Report Summary
Molecular mechanisms of general anesthetics on glutamate receptor channels : Identification of a site of action and examination of anesthetic behaviors in knock-out mice
| Project/Area Number |
10671407
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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 |
Anesthesiology/Resuscitation studies
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| Research Institution | Niigata University |
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Principal Investigator |
SHIBUE Chieko Medical Hospital, Niigata University, Lecturer, 医学部・附属病院, 助手 (90303148)
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| Co-Investigator(Kenkyū-buntansha) |
SAKIMURA Kenji Brain Research Institute, Niigata University, Professor, 脳研究所, 教授 (40162325)
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| Project Period (FY) |
1998 – 2000
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| Keywords | General anesthetics / Glutamate reveptor / NMDA receptor / Molecular biology / Site-directed mutagenesis / Knock-out mice |
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| Research Abstract |
Glutamate receptor channels mediate most of the fast excitatory synaptic transmission in the central nervous system. Recent studies suggest that inhibition of glutamate receptor channels is involved in mechanisms of actions of general anesthetics and sedatives. The present research examined the effects of general anesthetics on the recombinant glutamate receptor channels composed of various subunits. We also tested the importance of a certain amino acid residue of the subunit in the action of anesthetics by site-directed mutagenesis. Furthermore, to investigate a role of a certain subunit in the behavioral effects of general anesthetics in vivo, we examined anesthetic behaviors in the mice lacking the specific glutamate receptor channel subunit. We have found that butyrophenones selectively inhibit NMDA receptor channels composed of ε2 subunits. It was also found that opioid inhibits NMDA receptor channels at high concentrations which seem to be achieved in the cerebrospinal fluid after epidural or intrathecal administration of opioids, but seem to be higher than those observed in the blood during high dose opioid anesthesia for cardiac surgery. The action sites of butyrophenones and opioids partially overlapped with those of Mg^<2+> and dissociative anesthetics and mechanisms of these drugs involved the channel-block of the NMDA receptor channels. Furthermore, the anesthetic effects of ketamine measured by loss of righting reflex in mice lacking the ε1 subunit of the NMDA receptor channel were weaker than the wild-type mice, thus, anesthetic effects of ketamine might be mediated by the NMDA receptor channel composed of the ε1 subtunit. These results indicated the involvement of a specific subunit or a specific amino acid residue in the action mechanisms of anesthetics on glutamate receptor channels and in the anesthetic behavioral effects in vivo.
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