2024/04/22 更新

写真a

オオハシ ノブコ
大橋 宣子
OHASHI Nobuko
所属
医歯学総合病院 麻酔科 助教
職名
助教
外部リンク

学位

  • 博士(医学) ( 2016年3月   新潟大学 )

研究分野

  • ライフサイエンス / 麻酔科学

経歴

  • 新潟大学   医歯学総合病院 麻酔科   助教

    2016年4月 - 現在

所属学協会

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論文

  • Omega-conotoxin MVIIA reduces neuropathic pain after spinal cord injury by inhibiting N-type voltage-dependent calcium channels on spinal dorsal horn

    Nobuko Ohashi, Daisuke Uta, Masayuki Ohashi, Rintaro Hoshino, Hiroshi Baba

    Frontiers in Neuroscience   18   2024年2月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Frontiers Media SA  

    Spinal cord injury (SCI) leads to the development of neuropathic pain. Although a multitude of pathological processes contribute to SCI-induced pain, excessive intracellular calcium accumulation and voltage-gated calcium-channel upregulation play critical roles in SCI-induced pain. However, the role of calcium-channel blockers in SCI-induced pain is unknown. Omega-conotoxin MVIIA (MVIIA) is a calcium-channel blocker that selectively inhibits N-type voltage-dependent calcium channels and demonstrates neuroprotective effects. Therefore, we investigated spinal analgesic actions and cellular mechanisms underlying the analgesic effects of MVIIA in SCI. We used SCI-induced pain model rats and conducted behavioral tests, immunohistochemical analyses, and electrophysiological experiments (in vitro whole-cell patch-clamp recording and in vivo extracellular recording). A behavior study suggested intrathecal MVIIA administration in the acute phase after SCI induced analgesia for mechanical allodynia. Immunohistochemical experiments and in vivo extracellular recordings suggested that MVIIA induces analgesia in SCI-induced pain by directly inhibiting neuronal activity in the superficial spinal dorsal horn. In vitro whole-cell patch-clamp recording showed that MVIIA inhibits presynaptic N-type voltage-dependent calcium channels expressed on primary afferent Aδ-and C-fiber terminals and suppresses the presynaptic glutamate release from substantia gelatinosa in the spinal dorsal horn. In conclusion, MVIIA administration in the acute phase after SCI may induce analgesia in SCI-induced pain by inhibiting N-type voltage-dependent calcium channels on Aδ-and C-fiber terminals in the spinal dorsal horn, resulting in decreased neuronal excitability enhanced by SCI-induced pain.

    DOI: 10.3389/fnins.2024.1366829

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  • Analgesic effect of ivabradine against inflammatory pain mediated by hyperpolarization-activated cyclic nucleotide–gated cation channels expressed on primary afferent terminals in the spinal dorsal horn

    Nobuko Ohashi, Daisuke Uta, Masayuki Ohashi, Hiroshi Baba

    Pain   163 ( 7 )   1356 - 1369   2022年7月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Ovid Technologies (Wolters Kluwer Health)  

    DOI: 10.1097/j.pain.0000000000002523

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  • Norepinephrine restores inhibitory tone of spinal lamina X circuitry, thus contributing to analgesia against inflammatory pain

    Nobuko Ohashi, Daisuke Uta, Masayuki Ohashi, Hiroshi Baba

    Neuroscience   2022年3月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.neuroscience.2022.03.023

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  • Analgesic Effect of Acetaminophen: A Review of Known and Novel Mechanisms of Action. 査読

    Front Pharmacol   11 ( 580289 )   2020年11月

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    担当区分:筆頭著者  

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  • Optimal Position of Inferior Vena Cava Cannula in Pediatric Cardiac Surgery: A Prospective, Randomized, Controlled, Double-Blind Study 査読 国際誌

    Yutaka Seino, Nobuko Ohashi, Hidekazu Imai, Hiroshi Baba

    Journal of Cardiothoracic and Vascular Anesthesia   33 ( 5 )   1253 - 1259   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1053/j.jvca.2018.10.023

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  • Action of norepinephrine on lamina X of the spinal cord. 査読

    Neuroscience   1 ( 408 )   214 - 225   2019年

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    担当区分:筆頭著者  

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  • Pediatric Patients with High Pulmonary Arterial Pressure in Congenital Heart Disease Have Increased Tracheal Diameters Measured by Computed Tomography. 国際誌

    Nobuko Ohashi, Hidekazu Imai, Yutaka Seino, Hiroshi Baba

    Journal of cardiothoracic and vascular anesthesia   32 ( 4 )   1676 - 1681   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: Determination of the appropriate tracheal tube size using formulas based on age or height often is inaccurate in pediatric patients with congenital heart disease (CHD), particularly in those with high pulmonary arterial pressure (PAP). Here, the authors compared tracheal diameters between pediatric patients with CHD with high PAP and low PAP. DESIGN: Retrospective clinical study. SETTING: Hospital. PARTICIPANTS: Pediatric patients, from birth to 6 months of age, requiring general anesthesia and tracheal intubation who underwent computed tomography were included. Patients with mean pulmonary artery pressure >25 mmHg were allocated to the high PAP group, and the remaining patients were allocated to the low PAP group. The primary outcome was the tracheal diameter at the cricoid cartilage level, and the secondary goal was to observe whether the size of the tracheal tube was appropriate compared with that obtained using predictable formulas based on age or height. MEASUREMENTS AND MAIN RESULTS: The mean tracheal diameter was significantly larger in the high PAP group than in the low PAP group (p < 0.01). Pediatric patients with high PAP required a larger tracheal tube size than predicted by formulas based on age or height (p = 0.04 for age and height). CONCLUSIONS: Pediatric patients with high PAP had larger tracheal diameters than those with low PAP and required larger tracheal tubes compared with the size predicted using formulas based on age or height.

    DOI: 10.1053/j.jvca.2017.12.004

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  • The endogenous agonist, β-alanine, activates glycine receptors in rat spinal dorsal neurons. 国際誌

    Yutaka Seino, Nobuko Ohashi, Tatsuro Kohno

    Biochemical and biophysical research communications   500 ( 4 )   897 - 901   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    β-alanine is a structural analog of glycine and γ-aminobutyric acid (GABA) and is thought to be involved in the modulation of nociceptive information at the spinal cord. However, it is not known whether β-alanine exerts its effect in substantia gelatinosa (SG) neurons of the spinal dorsal horn, where glycine and GABA play an important role in regulating nociceptive transmission from the periphery. Here, we investigated the effects of β-alanine on inhibitory synaptic transmission in adult rat SG neurons using whole-cell patch-clamp. β-alanine dose-dependently induced outward currents in SG neurons. Current-voltage plots revealed a reversal potential at approximately -70 mV, which was close to the equilibrium potential of Cl-. Pharmacological analysis revealed that β-alanine activates glycine receptors, but not GABAA receptors. These results suggest that β-alanine hyperpolarizes the membrane potential of SG neurons by activating Cl- channels through glycine receptors. Our findings raise the possibility that β-alanine may modulate pain sensation through glycine receptors.

    DOI: 10.1016/j.bbrc.2018.04.183

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  • Intraoperative Detection of Persistent Endoleak by Detecting Residual Spontaneous Echocardiographic Contrast in the Aneurysmal Sac During Thoracic Endovascular Aortic Repair. 国際誌

    Hidekazu Imai, Nobuko Ohashi, Takayuki Yoshida, Takeshi Okamoto, Nobutaka Kitamura, Takahiro Tanaka, Hiroshi Baba

    Anesthesia and analgesia   125 ( 2 )   417 - 420   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Persistent endoleaks may lead to adverse events after endovascular aortic repair. We prospectively examined the relationship between intraoperative residual spontaneous echocardiographic contrast (SEC) within the aneurysmal sac and the incidence of postoperative endoleaks in 60 patients undergoing thoracic endovascular aortic repair. Patients with SEC had a higher incidence of postoperative endoleaks than did patients without SEC within a few days postoperatively (60.0% vs 12.5%, respectively; P < .001) and at 6 months postoperatively (40.0% vs 2.5%, respectively; P < .001). Intraoperative confirmation of the absence of SEC may identify patients at low risk for persistent endoleaks after thoracic endovascular aortic repair.

    DOI: 10.1213/ANE.0000000000002207

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  • Acetaminophen Metabolite N-Acylphenolamine Induces Analgesia via Transient Receptor Potential Vanilloid 1 Receptors Expressed on the Primary Afferent Terminals of C-fibers in the Spinal Dorsal Horn. 査読 国際誌

    Nobuko Ohashi, Daisuke Uta, Mika Sasaki, Masayuki Ohashi, Yoshinori Kamiya, Tatsuro Kohno

    Anesthesiology   127 ( 2 )   355 - 371   2017年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: The widely used analgesic acetaminophen is metabolized to N-acylphenolamine, which induces analgesia by acting directly on transient receptor potential vanilloid 1 or cannabinoid 1 receptors in the brain. Although these receptors are also abundant in the spinal cord, no previous studies have reported analgesic effects of acetaminophen or N-acylphenolamine mediated by the spinal cord dorsal horn. We hypothesized that clinical doses of acetaminophen induce analgesia via these spinal mechanisms. METHODS: We assessed our hypothesis in a rat model using behavioral measures. We also used in vivo and in vitro whole cell patch-clamp recordings of dorsal horn neurons to assess excitatory synaptic transmission. RESULTS: Intravenous acetaminophen decreased peripheral pinch-induced excitatory responses in the dorsal horn (53.1 ± 20.7% of control; n = 10; P < 0.01), while direct application of acetaminophen to the dorsal horn did not reduce these responses. Direct application of N-acylphenolamine decreased the amplitudes of monosynaptic excitatory postsynaptic currents evoked by C-fiber stimulation (control, 462.5 ± 197.5 pA; N-acylphenolamine, 272.5 ± 134.5 pA; n = 10; P = 0.022) but not those evoked by stimulation of Aδ-fibers. These phenomena were mediated by transient receptor potential vanilloid 1 receptors, but not cannabinoid 1 receptors. The analgesic effects of acetaminophen and N-acylphenolamine were stronger in rats experiencing an inflammatory pain model compared to naïve rats. CONCLUSIONS: Our results suggest that the acetaminophen metabolite N-acylphenolamine induces analgesia directly via transient receptor potential vanilloid 1 receptors expressed on central terminals of C-fibers in the spinal dorsal horn and leads to conduction block, shunt currents, and desensitization of these fibers.

    DOI: 10.1097/ALN.0000000000001700

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  • Administration of tranexamic acid to patients undergoing surgery for adolescent idiopathic scoliosis evokes pain and increases the infusion rate of remifentanil during the surgery. 国際誌

    Nobuko Ohashi, Masayuki Ohashi, Naoto Endo, Tatsuro Kohno

    PloS one   12 ( 3 )   e0173622   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: We recently reported that tranexamic acid (TXA) evokes pain in rats by inhibiting γ-aminobutyric acid and glycine receptors on neurons in the spinal dorsal horn. Although TXA is commonly used to reduce perioperative blood loss during various surgeries, its potential to induce intraoperative nociception, thereby increasing the need for more analgesics during surgery, has not been investigated. Therefore, this study aimed to investigate whether TXA evokes pain and increases the need for a higher infusion rate of remifentanil in patients undergoing surgery for adolescent idiopathic scoliosis (AIS). METHODS: Data were collected from patients with AIS who underwent posterior spinal fusion surgery from January 2008 to December 2015. All surgical procedures were performed under total intravenous anesthesia with propofol and remifentanil, by the same team of orthopedic surgeons and anesthesiologists at a single institution. Patients in the TXA group were administered TXA (loading and maintenance doses, 1000 mg and 100 mg/h) whereas those in the control group were not. Our primary outcome was the infusion rate of the intraoperative opioid analgesic remifentanil. RESULTS: The final analysis was based on data collected from 33 and 30 patients in the control and TXA groups, respectively. No differences were observed in the demographic data or the hemodynamic parameters between the two groups of patients. In the TXA group, the durations of surgery and anesthesia were shorter, intravascular fluid volume and total blood loss were lower, and the doses of fentanyl and ketamine administered were higher than they were in the control group (P < 0.05 for all). The mean infusion rate of intraoperative remifentanil was significantly higher in the TXA group than in the control group (control group: 0.23 ± 0.04 μg/kg/min; TXA group: 0.28 ± 0.12 μg/kg/min; P = 0.014). CONCLUSIONS: Patients who received TXA during the AIS surgery required a higher infusion rate of remifentanil, indicating that TXA evoked pain during the surgery.

    DOI: 10.1371/journal.pone.0173622

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  • Ultrasound-guided ilioinguinal/iliohypogastric block did not reduce emergence delirium after ambulatory pediatric inguinal hernia repair: a prospective randomized double-blind study.

    Nobuko Ohashi, Sadahei Denda, Kenta Furutani, Takayuki Yoshida, Yoshinori Kamiya, Reiko Komura, Hironobu Nishimaki, Yasushi Iinuma, Yutaka Hirayama, Shinichi Naitou, Koju Nitta, Hiroshi Baba

    Surgery today   46 ( 8 )   963 - 9   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: Emergence delirium (ED) is a common postoperative complication of ambulatory pediatric surgery done under general anesthesia with sevoflurane. However, perioperative analgesic techniques have been shown to reduce sevoflurane-induced ED. The primary objective of this investigation was to examine whether an ultrasound-guided ilioinguinal/iliohypogastric (II/IH) nerve block for ambulatory pediatric inguinal hernia repair could reduce the incidence of sevoflurane-induced ED. METHODS: The subjects of this prospective randomized double-blind study were 40 boys ranging in age from 1 to 6 years, who were scheduled to undergo ambulatory inguinal hernia repair. The patients were randomized to either receive or not to receive an ultrasound-guided II/IH nerve block (Group B and Group NB, respectively). General anesthesia was maintained with sevoflurane and nitrous oxide. The primary outcome assessed was ED, evaluated using the Pediatric Anesthesia Emergence Delirium (PAED) scale 30 min after emergence from general anesthesia. The secondary outcomes assessed were postoperative pain, evaluated using the Behavioral Observational Pain Scale (BOPS), and the amount of intra-operative sevoflurane given. RESULTS: The median PAED scale scores did not differ between Groups B and NB at 30 min (P = 0.41). BOPS scores also did not differ significantly between the groups, but the mean amount of intraoperative sevoflurane given was significantly lower in Group B than in Group NB (P < 0.01). CONCLUSIONS: Ultrasound-guided II/IH nerve block for ambulatory pediatric inguinal hernia repair did not reduce ED, but it did decrease the amount of intra-operative sevoflurane needed. CLINICAL TRIAL REGISTRATION: UMIN000008586.

    DOI: 10.1007/s00595-015-1280-6

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  • トラネキサム酸の脊髄後角を介する痛みの機序の解明 査読

    大橋 宣子, 佐々木 美佳, 大橋 正幸, 紙谷 義孝, 馬場 洋, 河野 達郎

    PAIN RESEARCH   31 ( 1 )   9 - 20   2016年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:(一社)日本疼痛学会  

    トラネキサム酸(TXA)の脊髄後角を介する痛みの機序について検討した。6〜8週齢のWistar系成熟雄性ラットを用いた。腰部脊椎(L4/5)を椎弓切除し、脊髄クモ膜下にポリエチレンカテーテルを留置した。脊髄クモ膜下投与は、術後3日以上経過してから、カテーテルより濃度の異なるTXAを投与した。腹腔内投与は、直接腹腔内へ濃度の異なるTXAを投与した。TXAは大脳皮質だけではなく、脊髄後角ニューロンへも作用し、シナプス後性にGABAAおよびグリシン受容体を直接的に抑制することで痛みを誘発した。TXAは、一次求心性線維のシナプス前終末には作用せず、興奮性介在ニューロンのGABAAおよびグリシン受容体をシナプス後性に抑制することで脱抑制を生じ、間接的に記録SGニューロンへの興奮性伝達を増強することで痛みを誘発した。TXAの灌流投与により脊髄後角浅層のpERKの発現が増加した。

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    その他リンク: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J02781&link_issn=&doc_id=20160414560002&doc_link_id=%2Fci3painr%2F2016%2F003101%2F002%2F0009-0020%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fci3painr%2F2016%2F003101%2F002%2F0009-0020%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  • Tranexamic acid evokes pain by modulating neuronal excitability in the spinal dorsal horn. 査読 国際誌

    Nobuko Ohashi, Mika Sasaki, Masayuki Ohashi, Yoshinori Kamiya, Hiroshi Baba, Tatsuro Kohno

    scientific reports   5 ( 13458 )   13458 - 13458   2015年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Tranexamic acid (TXA) is an antifibrinolytic agent widely used to reduce blood loss during surgery. However, a serious adverse effect of TXA is seizure due to inhibition of γ-aminobutyric acid (GABA) and glycine receptors in cortical neurons. These receptors are also present in the spinal cord, and antagonism of these receptors in spinal dorsal horn neurons produces pain-related phenomena, such as allodynia and hyperalgesia, in experimental animals. Moreover, some patients who are injected intrathecally with TXA develop severe back pain. However, the effect of TXA on spinal dorsal horn neurons remain poorly understood. Here, we investigated the effects of TXA by using behavioral measures in rats and found that TXA produces behaviors indicative of spontaneous pain and mechanical allodynia. We then performed whole-cell patch-clamp experiments that showed that TXA inhibits GABAA and glycine receptors in spinal dorsal horn neurons. Finally, we also showed that TXA facilitates activation of the extracellular signal-regulated kinase in the spinal cord. These results indicated that TXA produces pain by inhibiting GABAA and glycine receptors in the spinal dorsal horn.

    DOI: 10.1038/srep13458

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  • Anesthetic management in a patient with giant growing teratoma syndrome: A case report 査読

    Nobuko Ohashi, Hidekazu Imai, Toshiyuki Tobita, Hideaki Ishii, Hiroshi Baba

    Journal of Medical Case Reports   8 ( 1 )   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Introduction. Growing teratoma syndrome is a rare occurrence with an ovarian tumor. Anesthesia has been reported to be difficult in cases of growing teratoma syndrome of the cystic type due to the pressure exerted by the tumor. However, there have been no similar reports with the solid mass type. Here, we report our experience of anesthesia in a case of growing teratoma syndrome of the solid type. Case presentation. The patient was a 30-year-old Japanese woman who had been diagnosed with an ovarian immature teratoma at age 12 and had undergone surgery and chemotherapy. However, she dropped out of treatment. She presented to our hospital with a 40cm giant solid mass and severe respiratory failure, and was scheduled for an operation. We determined that we could not obtain a sufficient tidal volume without spontaneous respiration. Therefore, we chose to perform awake intubation and not to use a muscle relaxant before the operation. At the start of the operation, when muscle relaxant was first administered, we could not obtain a sufficient tidal volume. An abdominal midline incision was performed immediately and her tidal volume recovered. Her resected tumor weighed 10.5kg. After removal of her tumor, her tidal volume was maintained at a level consistent with that under spontaneous respiration to avoid occurrence of re-expansion pulmonary edema. Conclusions: We performed successful anesthetic management of a case of growing teratoma syndrome with a giant abdominal tumor. Respiratory management was achieved by avoiding use of a muscle relaxant before the operation to maintain spontaneous respiration and by maintaining a relatively low tidal volume, similar to that during spontaneous respiration preoperatively, after removal of the tumor to prevent re-expansion pulmonary edema. © 2014Ohashi et al.
    licensee BioMed Central Ltd.

    DOI: 10.1186/1752-1947-8-32

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  • 神経障害性疼痛患者に対するプレガバリン用量別の鎮痛効果と副作用 査読

    大橋宣子, 清水大喜, 生駒美穂, 岡本 学, 河野達郎, 馬場 洋

    日本ペインクリニック学会誌   20 ( 4 )   500 - 502   2013年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Japan Society of Pain Clinicians  

    DOI: 10.11321/jjspc.12-0045

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    その他リンク: https://jlc.jst.go.jp/DN/JALC/10025432663?from=CiNii

  • トラネキサム酸の脊髄後角を介する痛みの機序の解明

    大橋 宣子, 佐々木 美佳, 大橋 正幸, 紙谷 義孝, 馬場 洋, 河野 達郎

    PAIN RESEARCH   31 ( 1 )   9 - 20   2013年

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    記述言語:日本語   出版者・発行元:日本疼痛学会  

    Tranexamic acid (TXA) is an antifibrinolytic agent widely used to reduce blood loss during surgery. However, a serious adverse effect of TXA is seizure due to inhibition of γ–aminobutyric acid (GABA) and glycine receptors in cortical neurons. These receptors are also present in the spinal cord, and antagonism of these receptors in spinal dorsal horn neurons produces painrelated phenomena, such as allodynia and hyperalgesia. Moreover, some patients who are injected intrathecally with TXA develop severe back pain. However, no previous studies have investigated whether TXA modulates the GABA and glycine receptors in dorsal horn neurons. We hypothesized that TXA inhibits both GABA and glycine receptors in dorsal horn neurons,resulting in producing pain. Here, we investigated the effects of TXA by using behavioral measures in rats and found that TXA produces behaviors indicative of spontaneous pain and allodynia. We then performed wholecell patch–clamp experiments that showed that TXA inhibits GABAA and glycine receptors in spinal dorsal horn neurons. Finally, we also showed that TXA facilitates activation of the extracellular signal–regulated kinase in the spinal cord. These results indicated that TXA produces pain by inhibiting GABAA and glycine receptors directly located on postsynaptic sites of the recorded SG neurons. In addition, TXA enhances the excitability of excitatory interneurons via blockade of GABAergic and glycinergic postsynaptic inhibition, which facilitates excitatory transmission to the SG neurons indirectly.

    DOI: 10.11154/pain.31.9

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    その他リンク: http://search.jamas.or.jp/link/ui/2016213404

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書籍等出版物

  • トラネキサム酸による疼痛増強効果 -トラネキサム酸の脊髄後角を介する発痛作用の機序解明-

    Lisa: メディカル・サイエンス・インターナショナル  2018年 

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  • 神経障害性痛の発生機序 脊髄での機序

    痛みのScience & Practice 8  2015年 

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MISC

受賞

  • 有壬記念学術奨励賞

    2019年  

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  • 日本麻酔科学会第65回学術集会 若手奨励賞 (基礎)

    2018年   日本麻酔科学会  

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  • 新潟大学学長賞

    2018年   新潟大学  

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共同研究・競争的資金等の研究

  • イバブラジンの脊髄後角における作用機序解明と新規鎮痛薬としての有効性の検討

    研究課題/領域番号:22K09041

    2022年4月 - 2025年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    西塔 志乃, 大橋 宣子

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    配分額:4030000円 ( 直接経費:3100000円 、 間接経費:930000円 )

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  • 脊髄損傷後疼痛における脊髄のシナプス可塑性変化の病態解明

    研究課題/領域番号:22K09090

    2022年4月 - 2025年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    大橋 宣子, 馬場 洋

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    配分額:4030000円 ( 直接経費:3100000円 、 間接経費:930000円 )

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  • 脊髄損傷後疼痛におけるN型電位依存性Ca2+チャネルの役割と新規急性期治療の開発

    研究課題/領域番号:21K09272

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    大橋 正幸, 馬場 洋, 大橋 宣子

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    脊髄損傷は受傷時の脊髄への機械的損傷と、それに引き続く二次損傷により障害が重篤化することが知られている。二次障害においては細胞内Ca2+濃度上昇を伴う興奮毒性が関与しており、特にN型電位依存性Ca2+チャネルが重要な役割を担っている。そこで、ラット不全脊髄損傷モデルを用いて、脊髄損傷後急性期におけるN型電位依存性Ca2+チャネルの役割を運動および知覚機能の両面から解析した。脊髄損傷後4時間でN型電位依存性Ca2+チャネル阻害薬であるω-conotoxin MVIIAをくも膜下投与し、後肢運動機能 (Basso-Beattie-Bresnahan (BBB) score)と痛覚過敏 (von Frey test)を対照群と比較した。脊髄圧挫損傷を200kdyで加えた場合、後肢運動機能は損傷後3日の時点では投与群で有意にBBBスコアが高かったが、損傷後7日、14日では有意差を認めなかった。圧挫損傷100kdyでは、後肢運動機能は損傷後2日目を除いて損傷後1~7日まで投与群で有意にBBBスコアが高かったが、損傷後14日では有意差を認めなかった。また、von Frey testでは、損傷後14日の疼痛閾値は投与群で有意に高かった。以上から、脊髄損傷後急性期治療としてのN型電位依存性Ca2+チャネル阻害薬の有用性が、運動・知覚の両面から示唆された。一方で、運動機能に関しては損傷後1週間以降は投与群と対照群で有意差を認めなくなっており、次年度以降、複数回投与の効果についても検討予定である。また、本薬剤の効果について、電気生理学的実験、免疫組織学的実験、およびカルシウムイメージングにより多角的に検討を進める予定である。

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  • 脊髄Ⅹ層における慢性疼痛発症過程で生じるシナプス可塑性変化の病態解明

    研究課題/領域番号:20K17777

    2020年4月 - 2022年3月

    制度名:科学研究費助成事業 若手研究

    研究種目:若手研究

    提供機関:日本学術振興会

    大橋 宣子

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    本研究では慢性疼痛で生じるシナプス可塑性変化が脊髄Ⅹ層においても生じているか、炎症性疼痛モデルを用い脊髄Ⅹ層ニューロンにおけるノルアドレナリン (NA)の反応を検討した。
    痛み刺激により発現するリン酸化extracellular signal-regulated kinaseの増強をみとめ、in vivo脊髄細胞外記録による活動電位の発生頻度が増加したが、NAによりそれらの反応は抑制された。また脊髄後角におけるin vitroパッチクランプ記録では、NAはⅩ層の抑制性ニューロンシナプス前終末のα1A 受容体、およびシナプス後膜のα2受容体を活性化することで、炎症性疼痛に対し鎮痛効果を発揮した。

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  • 脊髄Ⅹ層におけるノルアドレナリンの作用機序と慢性疼痛の病態解明

    研究課題/領域番号:19K24008

    2019年8月 - 2021年3月

    制度名:科学研究費助成事業 研究活動スタート支援

    研究種目:研究活動スタート支援

    提供機関:日本学術振興会

    大橋 宣子

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    配分額:2860000円 ( 直接経費:2200000円 、 間接経費:660000円 )

    慢性疼痛患者は難治性の疾患であり、その機序解明と治療法の確立は極めて重要な課題である。一般的に慢性疼痛の発症には末梢だけでなく脊髄の形態学的、機能的変化も関与すると考えられており、脊髄ニューロンを含む神経系の興奮性が亢進した状態、すなわち可塑性変化として認められる。脊髄は形態学的所見によりⅠからⅩ層に分類され、末梢からの情報が各層に入力されるが、慢性疼痛時にはこれらの経路に脊髄レベルの可塑性変化が生じており、具体的にはⅠ層の長期増強現象 (LTP)、Ⅰ・Ⅱ層のAβ線維の軸索発芽、Ⅴ層のwind up現象などがあり、それぞれが層特異的に慢性疼痛の発症に関与している。その中でも代表的治療薬である抗うつ薬はノルアドレナリン (NA)の再取り込みを抑制するが、特に脊髄II層のNAを増加させることで鎮痛効果を発揮すると考えられてきた。一方、Ⅹ層は中心管周囲の灰白質として知られており、末梢から入力された情報はこのⅩ層へも到達した後、上行し視床、大脳皮質にある体性感覚野へ至ることが知られている。また近年、特にⅩ層はNAが最も多く分布することが明らかになり、X層が慢性疼痛の発症に大きく関与している可能性が示唆されたが、これまでにⅩ層の機能を検討した報告はない。そこで本研究ではまず慢性疼痛モデルラットとして炎症性疼痛モデルラットを作製し、疼痛モデルを確立した。そして炎症性疼痛モデルラットを用い、Ⅹ層におけるNAの作用をin vitro脊髄スライス標本からのパッチクランプ法を用いた電気生理学実験により検討した。その結果、NAは脊髄Ⅹ層の抑制性ニューロンにおける微小抑制性シナプス後電流 (mIPSC)の増強を認めた。つまり、Ⅹ層ではNAの放出を増加させ抑制性シナプス伝達を活性化することで、鎮痛効果をもたらしている可能性が示唆された。

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  • アセトアミノフェンの脊髄後角における鎮痛機序解明と新規投与経路の開発

    研究課題/領域番号:16K20081

    2016年4月 - 2018年3月

    制度名:科学研究費助成事業 若手研究(B)

    研究種目:若手研究(B)

    提供機関:日本学術振興会

    大橋 宣子

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    配分額:3900000円 ( 直接経費:3000000円 、 間接経費:900000円 )

    アセトアミノフェンの作用機序はN-アシルフェノールアミン (AM404)が脳に移行し、TRPV1やCB1受容体を活性化することで鎮痛作用を発揮するとされている。一方、このTRPV1やCB1受容体は脳だけでなく痛覚伝導路である脊髄後角にも多く存在するが、これまでにアセトアミノフェンの脊髄後角における鎮痛作用を検討した報告はない。そこで我々は、行動学実験およびin vivo、in vitroパッチクランプ記録を用いた電気生理学実験を行い、アセトアミノフェンはAM404へ代謝された後、脊髄後角ニューロンのC線維終末のTRPV1受容体に作用し脊髄レベルで鎮痛作用を発揮することを明らかにした。

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