Publications by authors named "Risako Kato"

12 Publications

  • Page 1 of 1

D-Amphetamine Rapidly Reverses Dexmedetomidine-Induced Unconsciousness in Rats.

Front Pharmacol 2021 18;12:668285. Epub 2021 May 18.

Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, United States.

D-amphetamine induces emergence from sevoflurane and propofol anesthesia in rats. Dexmedetomidine is an α-adrenoreceptor agonist that is commonly used for procedural sedation, whereas ketamine is an anesthetic that acts primarily by inhibiting NMDA-type glutamate receptors. These drugs have different molecular mechanisms of action from propofol and volatile anesthetics that enhance inhibitory neurotransmission mediated by GABA receptors. In this study, we tested the hypothesis that d-amphetamine accelerates recovery of consciousness after dexmedetomidine and ketamine. Sixteen rats (Eight males, eight females) were used in a randomized, blinded, crossover experimental design and all drugs were administered intravenously. Six additional rats with pre-implanted electrodes in the prefrontal cortex (PFC) were used to analyze changes in neurophysiology. After dexmedetomidine, d-amphetamine dramatically decreased mean time to emergence compared to saline (saline:112.8 ± 37.2 min; d-amphetamine:1.8 ± 0.6 min, < 0.0001). This arousal effect was abolished by pre-administration of the D/D dopamine receptor antagonist, SCH-23390. After ketamine, d-amphetamine did not significantly accelerate time to emergence compared to saline (saline:19.7 ± 18.0 min; d-amphetamine:20.3 ± 16.5 min, = 1.00). Prefrontal cortex local field potential recordings revealed that d-amphetamine broadly decreased spectral power at frequencies <25 Hz and restored an awake-like pattern after dexmedetomidine. However, d-amphetamine did not produce significant spectral changes after ketamine. The duration of unconsciousness was significantly longer in females for both dexmedetomidine and ketamine. In conclusion, d-amphetamine rapidly restores consciousness following dexmedetomidine, but not ketamine. Dexmedetomidine reversal by d-amphetamine is inhibited by SCH-23390, suggesting that the arousal effect is mediated by D and/or D receptors. These findings suggest that d-amphetamine may be clinically useful as a reversal agent for dexmedetomidine.
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http://dx.doi.org/10.3389/fphar.2021.668285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167047PMC
May 2021

Prehabilitation With Brain Stimulation?

Anesth Analg 2021 05;132(5):1344-1346

From the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1213/ANE.0000000000005454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054917PMC
May 2021

The Neural Circuits Underlying General Anesthesia and Sleep.

Anesth Analg 2021 05;132(5):1254-1264

From the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.

General anesthesia is characterized by loss of consciousness, amnesia, analgesia, and immobility. Important molecular targets of general anesthetics have been identified, but the neural circuits underlying the discrete end points of general anesthesia remain incompletely understood. General anesthesia and natural sleep share the common feature of reversible unconsciousness, and recent developments in neuroscience have enabled elegant studies that investigate the brain nuclei and neural circuits underlying this important end point. A common approach to measure cortical activity across the brain is electroencephalogram (EEG), which can reflect local neuronal activity as well as connectivity among brain regions. The EEG oscillations observed during general anesthesia depend greatly on the anesthetic agent as well as dosing, and only some resemble those observed during sleep. For example, the EEG oscillations during dexmedetomidine sedation are similar to those of stage 2 nonrapid eye movement (NREM) sleep, but high doses of propofol and ether anesthetics produce burst suppression, a pattern that is never observed during natural sleep. Sleep is primarily driven by withdrawal of subcortical excitation to the cortex, but anesthetics can directly act at both subcortical and cortical targets. While some anesthetics appear to activate specific sleep-active regions to induce unconsciousness, not all sleep-active regions play a significant role in anesthesia. Anesthetics also inhibit cortical neurons, and it is likely that each class of anesthetic drugs produces a distinct combination of subcortical and cortical effects that lead to unconsciousness. Conversely, arousal circuits that promote wakefulness are involved in anesthetic emergence and activating them can induce emergence and accelerate recovery of consciousness. Modern neuroscience techniques that enable the manipulation of specific neural circuits have led to new insights into the neural circuitry underlying general anesthesia and sleep. In the coming years, we will continue to better understand the mechanisms that generate these distinct states of reversible unconsciousness.
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http://dx.doi.org/10.1213/ANE.0000000000005361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054915PMC
May 2021

D-Amphetamine Accelerates Recovery of Consciousness and Respiratory Drive After High-Dose Fentanyl in Rats.

Front Pharmacol 2020 12;11:585356. Epub 2020 Nov 12.

Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, United States.

In the United States, fentanyl causes approximately 60,000 drug overdose deaths each year. Fentanyl is also frequently administered as an analgesic in the perioperative setting, where respiratory depression remains a common clinical problem. Naloxone is an efficacious opioid antagonist, but it possesses a short half-life and undesirable side effects. This study was conducted to test the hypothesis that d-amphetamine ameliorates respiratory depression and hastens the return of consciousness following high-dose fentanyl. Behavioral endpoints (first head movement, two paws down, and return of righting), arterial blood gas analysis and local field potential recordings from the prefrontal cortex were conducted in adult rats after intravenous administration of of fentanyl (55 µg/kg) at a dose sufficient to induce loss of righting and respiratory depression, followed by intravenous d-amphetamine (3 mg/kg) or saline (vehicle). D-amphetamine accelerated the time to return of righting by 36.6% compared to saline controls. D-amphetamine also hastened recovery of arterial pH, and the partial pressure of CO2, O2 and sO2 compared to controls, with statistically significant differences in pH after 5 min and 15 min. Local field potential recordings from the prefrontal cortex showed that within 5 min of d-amphetamine administration, the elevated broadband power <20 Hz produced by fentanyl had returned to awake baseline levels, consistent with the return of consciousness. Overall, d-amphetamine attenuated respiratory acidosis, increased arterial oxygenation, and accelerated the return of consciousness in the setting of fentanyl intoxication. This suggests that d-amphetamine may be a useful adjunct or alternative to opioid receptor antagonists such as naloxone.
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http://dx.doi.org/10.3389/fphar.2020.585356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793336PMC
November 2020

Manipulating Neural Circuits in Anesthesia Research.

Anesthesiology 2020 07;133(1):19-30

From the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts (E.D.M., O.A.M., K.N., R.K., C.J.N., K.S.) the Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts (E.D.M., O.A.M., R.K., C.J.N., K.S.) the Department of Brain and Cognitive Sciences (E.D.M., O.A.M., R.K., C.J.N., K.S.) the Institute for Medical Engineering and Science (K.N.), Massachusetts Institute of Technology, Cambridge, Massachusetts.

The neural circuits underlying the distinct endpoints that define general anesthesia remain incompletely understood. It is becoming increasingly evident, however, that distinct pathways in the brain that mediate arousal and pain are involved in various endpoints of general anesthesia. To critically evaluate this growing body of literature, familiarity with modern tools and techniques used to study neural circuits is essential. This Readers' Toolbox article describes four such techniques: (1) electrical stimulation, (2) local pharmacology, (3) optogenetics, and (4) chemogenetics. Each technique is explained, including the advantages, disadvantages, and other issues that must be considered when interpreting experimental results. Examples are provided of studies that probe mechanisms of anesthesia using each technique. This information will aid researchers and clinicians alike in interpreting the literature and in evaluating the utility of these techniques in their own research programs.
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http://dx.doi.org/10.1097/ALN.0000000000003279DOI Listing
July 2020

Propofol decreases spike firing frequency with an increase in spike synchronization in the cerebral cortex.

J Pharmacol Sci 2020 Mar 20;142(3):83-92. Epub 2019 Nov 20.

Department of Pharmacology, Nihon University School of Dentistry, Tokyo, Japan; Department of Pharmacology and Division of Oral and Craniomaxillofacial Research, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan; Molecular Dynamics Imaging Unit, RIKEN Center for Life Science Technologies, Kobe, Japan. Electronic address:

Little is known about how propofol modulates the spike firing correlation between excitatory and inhibitory cortical neurons in vivo. We performed extracellular unit recordings from rat insular cortical neurons, and classified neurons with high spontaneous firing frequency, bursting, and short spike width as high frequency with bursting neurons (HFB; pseudo fast-spiking GABAergic neurons) and other neurons with low spontaneous firing frequency and no bursting were classified as non-HFB. Intravenous administration of propofol (12 mg/kg) from the caudal vein reduced the firing frequency of HFB, whereas propofol initially increased (within 30 s) and then decreased the firing frequency of non-HFB. Both HFB and non-HFB spontaneous action potential discharge was depressed by propofol with a greater depression seen for HFB. Cross-correlograms and auto-correlograms demonstrated propofol-induced increases in the ratio of the peak, which were mostly observed around 0-10 ms divided to baseline amplitude. The analysis of interspike intervals showed a decrease in spike firing at 20-100 Hz and a relative increase at 8-15 Hz. These results suggest that propofol induces a larger suppression of firing frequency in HFB and an enhancement of synchronized neural activities in the α frequency band in the cerebral cortex (192 words).
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http://dx.doi.org/10.1016/j.jphs.2019.11.005DOI Listing
March 2020

Application of unfolding transformation in the random matrix theory to analyze in vivo neuronal spike firing during awake and anesthetized conditions.

J Pharmacol Sci 2018 Mar 2;136(3):172-176. Epub 2018 Feb 2.

Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo, Japan; Molecular Dynamics Imaging Unit, RIKEN Center for Life Science Technologies, Kobe, Hyogo, Japan. Electronic address:

General anesthetics decrease the frequency and density of spike firing. This effect makes it difficult to detect spike regularity. To overcome this problem, we developed a method utilizing the unfolding transformation which analyzes the energy level statistics in the random matrix theory. We regarded the energy axis as time axis of neuron spike and analyzed the time series of cortical neural firing in vivo. Unfolding transformation detected regularities of neural firing while changes in firing densities were associated with pentobarbital. We found that unfolding transformation enables us to compare firing regularity between awake and anesthetic conditions on a universal scale.
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http://dx.doi.org/10.1016/j.jphs.2018.01.004DOI Listing
March 2018

Phase-dependent activity of neurons in the rostral part of the thalamic reticular nucleus with saccharin intake in a cue-guided lever-manipulation task.

Brain Res 2017 03 13;1658:42-50. Epub 2017 Jan 13.

Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan; Division of Oral and Craniomaxillofacial Research, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan; Molecular Dynamics Imaging Unit, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. Electronic address:

Neurons in the rostral part of the thalamic reticular nucleus (rTRN) receive somatosensory and motor information and regulate neural activities of the thalamic nuclei. Previous studies showed that when activity in visual TRN neurons is suppressed prior to the visual stimuli in a visual detection task, the performance of the task improves. However, little is known about such changes in the rTRN preceding certain events. In the present study, we performed unit recordings in the rTRN in alert rats during a cue-guided lever-manipulation task in which saccharin was provided as a reward. Changes in neural activity during saccharin intake were observed in 56% (51 of 91) of the recorded neurons; the firing rates increased in 21 neurons and decreased in 23 neurons. Seven neurons both increased and decreased their firing rates during saccharin intake. Changes in firing rates during the reward-waiting stage between task termination and saccharin intake were also observed in 73% (37 of 51) of the neurons that responded to saccharin intake. Increased activity during saccharin intake did not correlate with increased activity during lever-manipulation or activity during the reward-waiting stage. However, decreased activity during saccharin intake was correlated with activity during the reward-waiting stage. These results suggest that rTRN neurons have phase-dependent changes in their activity and regulate the thalamic activities. Furthermore, the decreased activity of rTRN neurons before reward may contribute to refine somatosensory and motor information processing in the thalamic nuclei depending on the status of mind such as expectation and attention.
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http://dx.doi.org/10.1016/j.brainres.2017.01.013DOI Listing
March 2017

Spike Timing Rigidity Is Maintained in Bursting Neurons under Pentobarbital-Induced Anesthetic Conditions.

Front Neural Circuits 2016 14;10:86. Epub 2016 Nov 14.

Department of Pharmacology, School of Dentistry, Nihon UniversityChiyoda, Japan; Division of Oral and Craniomaxillofacial Research, Dental Research Center, School of Dentistry, Nihon UniversityChiyoda, Japan; Molecular Dynamics Imaging Unit, RIKEN Center for Life Science TechnologiesKobe, Japan.

Pentobarbital potentiates γ-aminobutyric acid (GABA)-mediated inhibitory synaptic transmission by prolonging the open time of GABA receptors. However, it is unknown how pentobarbital regulates cortical neuronal activities via local circuits . To examine this question, we performed extracellular unit recording in rat insular cortex under awake and anesthetic conditions. Not a few studies apply time-rescaling theorem to detect the features of repetitive spike firing. Similar to these methods, we define an average spike interval locally in time using random matrix theory (RMT), which enables us to compare different activity states on a universal scale. Neurons with high spontaneous firing frequency (>5 Hz) and bursting were classified as HFB neurons ( = 10), and those with low spontaneous firing frequency (<10 Hz) and without bursting were classified as non-HFB neurons ( = 48). Pentobarbital injection (30 mg/kg) reduced firing frequency in all HFB neurons and in 78% of non-HFB neurons. RMT analysis demonstrated that pentobarbital increased in the number of neurons with repulsion in both HFB and non-HFB neurons, suggesting that there is a correlation between spikes within a short interspike interval (ISI). Under awake conditions, in 50% of HFB and 40% of non-HFB neurons, the decay phase of normalized histograms of spontaneous firing were fitted to an exponential function, which indicated that the first spike had no correlation with subsequent spikes. In contrast, under pentobarbital-induced anesthesia conditions, the number of non-HFB neurons that were fitted to an exponential function increased to 80%, but almost no change in HFB neurons was observed. These results suggest that under both awake and pentobarbital-induced anesthetized conditions, spike firing in HFB neurons is more robustly regulated by preceding spikes than by non-HFB neurons, which may reflect the GABA receptor-mediated regulation of cortical activities. Whole-cell patch-clamp recording in the IC slice preparation was performed to compare the regularity of spike timing between pyramidal and fast-spiking (FS) neurons, which presumably correspond to non-HFB and HFB neurons, respectively. Repetitive spike firing of FS neurons exhibited a lower variance of ISI than pyramidal neurons both in control and under application of pentobarbital, supporting the above hypothesis.
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http://dx.doi.org/10.3389/fncir.2016.00086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107820PMC
October 2017

Spatiotemporal profiles of dental pulp nociception in rat cerebral cortex: an optical imaging study.

J Comp Neurol 2015 Jun 16;523(8):1162-74. Epub 2015 Mar 16.

Department of Pharmacology, Nihon University School of Dentistry, Tokyo, 101-8310, Japan; Department of Pediatric Dentistry, Nihon University School of Dentistry, Tokyo, 101-8310, Japan.

Somatosensation is topographically organized in the primary (S1) and secondary somatosensory cortex (S2), which contributes to identify the region receiving sensory inputs. However, it is still unknown how somatosensory inputs from the oral region, especially nociceptive inputs from the teeth, are processed in the somatosensory cortex. We performed in vivo optical imaging and identified the precise cortical regions responding to electrical stimulation of the maxillary and mandibular dental pulp in rats. Electrical stimulation of the mandibular incisor pulp evoked neural excitation in two areas: the most rostroventral part of S1, and the ventral part of S2 caudal to the middle cerebral artery. Maxillary incisor pulp stimulation initially evoked responses only in the ventral part of S2, although later maximum responses were also observed in S1 similar to mandibular incisor stimulation responses. The maxillary and mandibular molar pulp-responding regions were located in the most ventral S2, a part of which was histologically classified as the insular oral region (IOR). In terms of the initial responses, maxillary incisor and molar stimulation induced excitation in the S2/IOR rostral to the mandibular dental pulp-responding region. Contrary to the spatially segregated initial responses, the maximum excitatory areas responding to both incisors and molars in the mandible and maxilla overlapped in S1 and the S2/IOR. Multielectrode extracellular recording supported the characteristic localization of S2/IOR neurons responding to mandibular and maxillary molar pulp stimulation. The discrete and overlapped spatial profiles of initial and maximum responses, respectively, may characterize nociceptive information processing of dental pain in the cortex.
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http://dx.doi.org/10.1002/cne.23692DOI Listing
June 2015

Apomorphine-induced modulation of neural activities in the ventrolateral striatum of rats.

Synapse 2013 Jul 7;67(7):363-73. Epub 2013 Mar 7.

Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-8310, Japan.

The dopaminergic system in the ventrolateral portion of the striatum (Svl), part of the basal ganglia, regulates orofacial movements; bilateral co-stimulation of both dopamine D1 -like and D2 -like receptors elicits repetitive jaw movements in rats. However, how the activities of Svl neurons are modulated by the activation of dopaminergic receptors remains unknown. We systematically injected apomorphine, a non-selective dopamine receptor agonist that induced jaw movements under urethane anesthesia, and performed multi-channel unit recording from Svl neurons. The Svl neurons were classified into two subgroups: (1) the phasically active (PA) neurons represented by mainly the medium spiny neurons and the GABAergic interneurons in part, and (2) the tonically active (TA) neurons composed of mainly the cholinergic interneurons. Apomorphine modulated PA neuron firing frequency with wide variability; 33.3% of the PA neurons were facilitated, while 38.3% were suppressed. In the majority of TA neurons, the firing frequency was reduced by apomorphine (71.1%). The cross-correlations between PA and PA, PA and TA, and TA and TA neurons were analyzed, and pairs of PA neurons and pairs of PA and TA neurons, showed negligible apomorphine-induced effect on the number of synchronized spikes. In contrast, pairs between TA neurons showed a consistent decrease in the number of synchronized spikes. The apomorphine-induced suppression of TA neuron activities with decreased synchronized outputs is likely to reduce the amount of locally released acetylcholine, which may contribute to the induction of apomorphine-induced jaw movements in rats.
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http://dx.doi.org/10.1002/syn.21644DOI Listing
July 2013

Effect of pamamycin-607 on secondary metabolite production by Streptomyces spp.

Biosci Biotechnol Biochem 2011 7;75(9):1722-6. Epub 2011 Sep 7.

Department of Plant Production, United Graduate School of Agricultural Sciences, Tokyo University of Agriculture and Technology.

The effect of the aerial mycelium-inducing compound, pamamycin-607, on antibiotic production by several Streptomyces spp. was examined. Exposure to 6.6 µM pamamycin-607 stimulated by 2.7 fold the puromycin production by Streptomyces alboniger NBRC 12738, in which pamamycin-607 had first been isolated, and restored aerial mycelium formation. Pamamycin-607 also stimulated the respective production of streptomycin by S. griseus NBRC 12875 and that of cinerubins A and B by S. tauricus JCM 4837 by approximately 1.5, 1.7 and 1.9 fold. The antibiotic produced by Streptomyces sp. 91-a was identified as virginiamycin M(1), and its synthesis was enhanced 2.6 fold by pamamycin-607. These results demonstrate that pamamycin-607 not only restored or stimulated aerial mycelium formation, but also stimulated secondary metabolite production.
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http://dx.doi.org/10.1271/bbb.110251DOI Listing
January 2012