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ANESTHETIC PHARMACOLOGY

Orexin A Decreases Ketamine-Induced Anesthesia Time in the Rat: The Relevance to Brain Noradrenergic Neuronal Activity

Ryuji Tose, MD^*, Tetsuya Kushikata, MD^*, Hitoshi Yoshida, MD^*, Mihoko Kudo, PhD^*, Kenichi Furukawa, PhD, Shinya Ueno, MD, and Kazuyoshi Hirota, MD, FRCA^*

From the Departments of *Anesthesiology, Pharmacology, and Rehabilitation Medicine, Institute of Brain Science, University of Hirosaki School of Medicine, Hirosaki, Japan.

Address correspondence and reprint requests to Ryuji Tose, MD, Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki 036-8563, Japan. Address e-mail to masuika{at}cc.hirosaki-u.ac.jp.

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 IC₅₀ values.

CONCLUSION: Orexinergic neurons may be an important target for ketamine. OXA antagonized ketamine anesthesia via Orexin-1 receptor with noradrenergic neurons.