Kenichi Furukawa

Hirosaki University, Khirosaki, Aomori, Japan

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Publications (4)11.82 Total impact

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    ABSTRACT: Urotensin II (UII) and its receptor (UT) are implicated in mood disorders, such as stress and anxiety, and this may result, at least in part, from increased norepinephrine release from the cerebral cortex. Benzodiazepines have been widely used as hypnotics and anxiolytics, producing a decrease in cerebrocortical norepinephrine release. We hypothesized that there was some interaction between benzodiazepines and the UII system in the cerebral cortex. In the present study, we have examined the effects of benzodiazepines on UII-increased norepinephrine release from rat cerebrocortical slices and intracellular Ca(2+) concentrations ([Ca(2+)]i) in HEK293 cells expressing rat UT receptor (HEK293-rUT cells). Midazolam, diazepam and flunitrazepam concentration-dependently inhibited UII-evoked norepinephrine release but did not affect [Ca(2+)]i. The IC(50) of midazolam for inhibition of UII-evoked norepinephrine release (0.32 microM, P < 0.01) was significantly lower than that of diazepam (187 microM) or flunitrazepam (40 microM). The inhibitory effects of midazolam on UII-evoked norepinephrine release were significantly attenuated by flumazenil, a benzodiazepine site antagonist. The present study suggests that midazolam, at clinically relevant concentration, significantly inhibited UII-evoked norepinephrine release. This inhibitory effect may be partially mediated via central benzodiazepine receptors.
    No preview · Article · Apr 2009 · Anesthesia and analgesia
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    ABSTRACT: 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. 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. 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. Orexinergic neurons may be an important target for ketamine. OXA antagonized ketamine anesthesia via Orexin-1 receptor with noradrenergic neurons.
    No preview · Article · Mar 2009 · Anesthesia and analgesia
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    ABSTRACT: Several studies suggest that NMDA glutamate receptors may play an important role in the activation of a number of brain regions by orexin (OX). We hypothesized that OX and NMDA receptors may interact with cerebrocortical noradrenergic neuron originating from the locus coeruleus (LC). To test this hypothesis, using rats as experimental animals, we examined (i) in vitro effects of MK801 on OXA-evoked norepinephrine release from rat cerebrocortical slices, (ii) in vivo interaction between OXA and the NMDA receptor antagonist, MK801 on norepinephrine release from the prefrontal cortex assessed using microdialysis and (iii) MK801 and OXA-modulation of the electroencephalogram (EEG). We have found that MK801 produced a concentration-dependent inhibition of OXA-evoked norepinephrine release from rat cerebrocortical slices with the IC(50) of 0.9 microM. Moreover, we have also found that icv OXA dose-dependently stimulated norepinephrine release from the rat prefrontal cortex saturating at 213% of baseline. In addition, ip MK801 0.1 mg/kg also significantly increased norepinephrine release in prefrontal cortex to 213%. However, these increases in norepinephrine release were significantly reduced by approximately 70% by simultaneous administration of icv OXA 1 nmol and ip MK801 0.1 mg/kg. Both OXA and MK801 decreased sleep and increased wakefulness, but co-administration caused a return to base-line sleep state. These findings strongly indicate that there is a significant interaction between orexinergic neurons and NMDA receptors in the control of LC-cerebrocortical noradrenergic activity.
    No preview · Article · Nov 2008 · Brain research
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    ABSTRACT: Urotensin II (UII) has been reported to modulate rapid eye movement (REM) sleep via activation of brainstem cholinergic neurons and REM sleep is regulated by locus coerleus (LC)-cerebrocortical noradrenergic neurons. We hypothesized that UII may activate LC-cerebrocortical noradrenergic neurons. To test this hypothesis, we have examined the effects of UII on norepinephrine release from rat cerebrocortical slices. In addition, the effect of the putative UT receptor antagonist [Pen(5), DTrp(7), Dab(8)]UII(4-11) (UFP-803) was assessed. We have compared this with other wakefulness-promoting neurotransmitters such as dopamine, glutamate, serotonin and histamine. We also studied the effects of UII and UFP-803 on intracellular Ca(2+) ([Ca(2+)]i) in HEK293 cells stably expressing rat UT receptor (HEK293-rUT cells). UII produced a time- (peaking at approximately 10 min following stimulation with 10nM) and concentration-dependent increase in norepinephrine release with pEC(50) and E(max) (% of basal) values of 8.78+/-0.17 (1.65 nM) and 138+/-2%, respectively. UII also evoked dopamine, serotonin and histamine release with similar pEC(50) values. UII increased glutamate release but only at high concentrations (<100 nM) and this failed to saturate. UII markedly increased [Ca(2+)](i) in HEK293-rUT cells in a concentration-dependent manner with pEC(50) of 8.26+/-0.24. The UT antagonist UFP-803 reversed both UII-increased norepinephrine release from the cerebrocortical slices (pK(B)=8.98) and [Ca(2+)](i) (pK(B)=8.87) in HEK293-rUT cells. Collectively these data suggest that UII evokes the release of norepinephrine via UT receptor activation and produces similar effects on other wakefulness-promoting neurotransmitters: these neurochemical actions of UII may be important for the control of the sleep-wake cycle.
    No preview · Article · Sep 2008 · Neuroscience Letters