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Increased brain monoaminergic tone after the NMDA receptor GluN2A subunit gene knockout is responsible for resistance to the hypnotic effect of nitrous oxide.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2013 Jan 05; Vol. 698 (1-3), pp. 200-5. Date of Electronic Publication: 2012 Nov 02. - Publication Year :
- 2013
-
Abstract
- N-methyl-d-aspartate (NMDA) receptors can be inhibited by inhalational anesthetics in vitro at clinically relevant concentrations. Here, to clarify the role of NMDA receptors in anesthetic-induced unconsciousness, we examined the hypnotic properties of isoflurane, sevoflurane and nitrous oxide in NMDA receptor GluN2A subunit knockout mice. The hypnotic properties of inhalational anesthetics were evaluated in mice in the loss of righting reflex (LORR) assay by measuring the 50% concentration for LORR (LORR ED(50)). Knockout mice displayed isoflurane and sevoflurane LORR ED(50) values similar to wild-type controls, indicating no significant contribution of these receptors to the hypnotic action of halogenated anesthetics. However, compared with wild-type controls, mutant mice displayed larger isoflurane LORR ED(50) values in the presence of nitrous oxide, indicating a resistance to this gaseous anesthetic. Knockout mice have enhanced brain monoaminergic activity which occurs secondary to NMDA receptor dysfunction, and the observed resistance to the isoflurane LORR ED(50)-sparing effect of nitrous oxide could be abolished by pretreatment with the dopamine D(2) receptor antagonist droperidol or with the serotonin 5-HT(2A) receptor antagonist ketanserin. Thus, resistance to nitrous oxide in knockout mice appears to be a secondary phenomenon of monoaminergic origin and not a direct result of impaired NMDA receptor function. Our results indicate that NMDA receptors are not critically involved in the hypnotic action of conventionally-used inhalational anesthetics. Also, they suggest that increased brain monoaminergic tone can diminish the effects of general anesthesia. Finally, they provide further evidence that changes secondary to genetic manipulation can explain the results obtained in global knockouts.<br /> (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Subjects :
- Anesthetics chemistry
Anesthetics pharmacology
Animals
Biogenic Monoamines antagonists & inhibitors
Droperidol pharmacology
Gene Knockout Techniques
Halogenation
Hypnotics and Sedatives chemistry
Hypnotics and Sedatives pharmacology
Ketanserin pharmacology
Male
Mice
Mice, Inbred C57BL
Nitrous Oxide chemistry
Reflex, Righting drug effects
Unconsciousness chemically induced
Biogenic Monoamines metabolism
Brain drug effects
Brain metabolism
Drug Resistance genetics
Nitrous Oxide pharmacology
Receptors, N-Methyl-D-Aspartate deficiency
Receptors, N-Methyl-D-Aspartate genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 698
- Issue :
- 1-3
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 23123346
- Full Text :
- https://doi.org/10.1016/j.ejphar.2012.10.034