Orexin A decreases ketamine-induced anesthesia time in the rat: the relevance to brain noradrenergic neuronal activity.
BACKGROUND
Orexins (OXs) regulate wakefulness, and a lack of OX Type-I receptors cause narcolepsy. OX selectively increases norepinephrine (NE) release from rat cerebral cortical slices, and brain noradrenergic neurons are involved in the sleep-wakefulness cycle. Ketamine increases NE release from the rat cerebral cortex. We hypothesized that OX would affect ketamine anesthesia's interactions with brain noradrenergic neuronal activity.


METHODS
We used Sprague Dawley rats. We studied 1) in vivo effects of orexin A (OXA) and SB-334867-A (Orexin-1 receptor antagonist) on ketamine-induced anesthesia time, 2) in vivo effects of OXA on ketamine-induced increase in NE release from the frontal cortex assessed using microdialysis, and 3) in vitro effects of ketamine on OXA-evoked NE release from rat cerebrocortical slices.


RESULTS
1) Intracerebroventricular OXA 1 nmol significantly decreased ketamine anesthesia time by 20%-30% at 50, 100, and 125 mg/kg intraperitoneal (IP) ketamine. SB-334867-A fully reversed the decrease produced by OXA. 2) OXA also decreased the release of NE induced by ketamine even though OXA increased the release of NE in rat prefrontal cortex. Maximum NE release in Group OX + K (intracerebroventricular OXA 1 nmol + IP ketamine 100 mg/kg) was 271% and was significantly smaller than that in Group K (ketamine 100 mg/kg IP, 390% of baseline, P = 0.029). 3) Ketamine inhibited OX-evoked NE release with clinically relevant IC(50) values.


CONCLUSIONS
Orexinergic neurons may be an important target for ketamine. OXA antagonized ketamine anesthesia via Orexin-1 receptor with noradrenergic neurons.
Tose
Ryuji
R
Department of Anesthesiology, Institute of Brain Science, University of Hirosaki School of Medicine, Hirosaki, Japan.
Kushikata
Tetsuya
T
Yoshida
Hitoshi
H
Kudo
Mihoko
M
Furukawa
Kenichi
K
Ueno
Shinya
S
Hirota
Kazuyoshi
K
D000758:Anesthesia; D000778:Anesthetics, Dissociative / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D007649:Ketamine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009287:Naphthyridines; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009479:Neuropeptides / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism / Q000502:physiology*; D000068797:Orexins; D051381:Rats; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D000778:Anesthetics, Dissociative; D001583:Benzoxazoles; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D000068797:Orexins; D018013:Receptors, Neuropeptide; D007649:Ketamine; D014508:Urea; D009638:Norepinephrine