Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：克誠堂出版(株)  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Mirror image pain (MIP) is a type of extraterritorial pain that results in contralateral pain or allodynia. Glutamate transporter-1 (GLT-1) is expressed in astrocytes and plays a role in maintaining low glutamate levels in the synaptic cleft. Previous studies have shown that GLT-1 dysfunction induces neuropathic pain. Our previous study revealed bilateral GLT-1 downregulation in the spinal cord of a spared nerve injury (SNI) rat. We hypothesized that spinal GLT-1 is involved in the mechanism of MIP. We also previously demonstrated noradrenergic GLT-1 regulation. Therefore, this study aimed to investigate the effect of an α1 adrenergic antagonist on the development of MIP. Rats were subjected to SNI. Changes in pain behavior and GLT-1 protein levels in the SNI rat spinal cords were then examined by intrathecal administration of the α1 adrenergic antagonist phentolamine, followed by von Frey test and western blotting. SNI resulted in the development of MIP and bilateral downregulation of GLT-1 protein in the rat spinal cord. Intrathecal phentolamine increased contralateral GLT-1 protein levels and partially ameliorated the 50% paw withdrawal threshold in the contralateral hind paw. Spinal GLT-1 upregulation by intrathecal phentolamine ameliorates MIP. GLT-1 plays a role in the development of MIPs.

DOI： 10.18926/AMO/63719

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Language：English   Publishing type：Research paper (scientific journal)  

The issue of tolerance to continuous or repeated administration of opioids should be addressed. The ability of ketamine to improve opioid tolerance has been reported in clinical studies, and its mechanism of tolerance may involve improved desensitization of μ-opioid receptors (MORs). We measured changes in MOR activity and intracellular signaling induced by repeated fentanyl and morphine administration and investigated the effects of ketamine on these changes with human embryonic kidney 293 cells expressing MOR using the CellKey™, cADDis cyclic adenosine monophosphate, and PathHunter® β-arrestin recruitment assays. Repeated administration of fentanyl or morphine suppressed the second MOR responses. Administration of ketamine before a second application of opioids within clinical concentrations improved acute desensitization and enhanced β-arrestin recruitment elicited by fentanyl but not by morphine. The effects of ketamine on fentanyl were suppressed by co-treatment with an inhibitor of G-protein-coupled receptor kinase (GRK). Ketamine may potentially reduce fentanyl tolerance but not that of morphine through modulation of GRK-mediated pathways, possibly changing the conformational changes of β-arrestin to MOR.

DOI： 10.3390/biom12030426

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Authorship：Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

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Microglia maintain central nervous system homeostasis by monitoring changes in their environment (resting state) and by taking protective actions to equilibrate such changes (activated state). These surveillance and protective roles both require constant movement of microglia. Interestingly, induced hypothermia can reduce microglia migration caused by ischemia, suggesting that microglia movement can be modulated by temperature. Although several ion channels and transporters are known to support microglia movement, the precise molecular mechanism that regulates temperature-dependent movement of microglia remains unclear. Some members of the transient receptor potential (TRP) channel superfamily exhibit thermosensitivity and thus are strong candidates for mediation of this phenomenon. Here, we demonstrate that mouse microglia exhibit temperature-dependent movement in vitro and in vivo that is mediated by TRPV4 channels within the physiological range of body temperature. Our findings may provide a basis for future research into the potential clinical application of temperature regulation to preserve cell function via manipulation of ion channel activity.

DOI： 10.1073/pnas.2012894118

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BACKGROUND: Intraoperative complications during combined thoracoscopic-laparoscopic surgery for esophagogastric junction (EGJ) carcinoma have not been reported as compared to those during surgery for esophageal carcinoma. We present two cases which had surgery-related hemodynamic instability during laparoscopic proximal gastrectomy and intra-mediastinal valvuloplastic esophagogastrostomy (vEG) with thoracoscopic mediastinal lymphadenectomy for EGJ carcinoma. CASE PRESENTATION: In case 1, the patient fell into hypotension with hypoxemia during laparoscopic vEG due to pneumothorax caused by entry of intraabdominal carbon dioxide. In case 2, ventricular arrythmia and ST elevation occurred during laparoscopic vEG. Pericardium retraction to secure surgical field during reconstruction compressed the coronary artery, which caused coronary malperfusion. These two events were induced by the surgical procedure, characterized by the following: (1) connection of the thoracic and abdominal cavities and (2) cardiac displacement during vEG. CONCLUSION: These cases indicated tension pneumothorax and coronary ischemia are possible intraoperative complications specific to combined thoracoscopic-laparoscopic surgery for EGJ carcinoma.

DOI： 10.1186/s40981-021-00419-x

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Authorship：Corresponding author   Language：Japanese   Publisher：日本臨床麻酔学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Sodium-channel myotonia (SCM) is a nondystrophic myotonia, characterized by pure myotonia without muscle weakness or paramyotonia. The prevalence of skeletal muscle channelopathies is approximately 1 in 100,000, and the prevalence of SCM is much lower. To our knowledge, this is the first report on anesthetic management of a patient with SCM. CASE PRESENTATION: A 23-year-old woman with congenital nasal dysplasia and SCM was scheduled to undergo rhinoplasty with autologous costal cartilage. Total intravenous anesthesia without muscle relaxants was administered followed by continuous intercostal nerve block. Although transient elevation of potassium level in the blood was observed during surgery, the patient did not show exacerbation of myotonic or paralytic symptoms in the postoperative period. CONCLUSION: Total intravenous anesthesia and peripheral nerve block can be administered safely to a patient with SCM. However, careful monitoring of the symptoms and electrolytes is recommended.

DOI： 10.1186/s40981-019-0300-8

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Language：Japanese   Publisher：日本小児麻酔学会  

症例は1歳11ヵ月の男児、声門下狭窄に対して輪状軟骨前方切開術が予定された。術中管理の問題点として、Tチューブ挿入後の陽圧換気中のTチューブ口側断端からのエアリークが挙げられたため、Tチューブ内にTチューブ径より小径の挿管チューブを経鼻的に留置し、挿管チューブをクランプすることで口側断端を塞ぐ方法を計画した。しかしスペースが小さく留置困難だったため、経鼻的にFogartyカテーテルをTチューブ内に留置し、バルーン拡張にて口側断端からのエアリークを軽減し、確実に換気することができた。Tチューブ挿入下での呼吸管理において、位置調整など慎重な管理は必要となるが、小児症例ではFogartyカテーテルを用いた換気方法は有用性が高いと考える。(著者抄録)

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are glycoproteins N-glycosylated at a specific asparagine residue in the S5-S6 linker region. Previous reports suggested that N-glycosylation-deficient HCN2 N380Q (NQ) channels fail to properly target to the plasma membrane and are unable to form functional ion channels. HCN channels are known to homo- and hetero-oligomerize and it is not known whether HCN2-NQ subunits can oligomerize with wild type (wt) N-glycosylated subunits to form a tetrameric assembly. In the present study, homomeric NQ-mutant resulted in no current, cRNA titration experiments controlling the amount of wt-to-NQ injected into Xenopus oocytes indicated that the observed currents were consistent with a model where presence of a single nonglycosylated subunit in a tetrameric oligomer is tolerated forming functional channels. The activation voltage-dependence described by half-activation voltage and slope factor, and the reversal potential of the wt-NQ oligomeric channels were identical to the wt only tetrameric channels. Further incorporation of the nonglycosylated subunit rendered the channels nonconductive or not incorporated into the plasma membrane.

DOI： 10.1097/WNR.0000000000001310

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Morphine, fentanyl, and oxycodone are widely used as analgesics, and recently hydromorphone has been approved in Japan. Although all of these are selective for μ-opioid receptors (MORs) and have similar structures, their analgesic potencies and adverse effects (AEs) are diverse. Recent molecular analyses of MOR signaling revealed that the G protein-mediated signaling pathway causes analgesic effects and the β-arrestin-mediated signaling pathway is responsible for AEs. We used several cell-based analyses that selectively measure cellular responses activated by either G protein- or β-arrestin-mediated pathways. GloSensor™ cAMP, CellKey™, and receptor internalization assays were performed with four different types of cells stably expressing differentially labelled MOR. EC50 values measured by cAMP and CellKey™ assays had potencies in the order fentanyl ≤ hydromorphone < morphine ≤ oxycodone, all also exhibiting full agonist responses. However, in the internalization assay, only fentanyl elicited a full agonist response. Hydromorphone had the strongest potency next to fentanyl; however, contribution of the β-arrestin-mediated pathway was small, suggesting that its effect could be biased toward the G protein-mediated pathway. Based on these properties, hydromorphone could be chosen as an effective analgesic.

DOI： 10.1016/j.jphs.2019.06.005

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Authorship：Lead author,　Corresponding author  

DOI： 10.1253/circj.CJ-18-0729

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Quercetin is a flavonoid widely found in plants and marketed to the public as a supplement. Several studies have reported its effect on glial cells. This study aimed to examine the effect of quercetin on the development of neuropathic pain and the underlying mechanism in a spared nerve injury (SNI) rat model. Male Sprague-Dawley rats randomly assigned to the control or the quercetin group were subjected to SNI of the sciatic nerve. We measured pain behaviors on the hind paw and glial fibrillary acidic protein (GFAP) in the dorsal root ganglion (DRG) and spinal cord. Oral administration of 1% quercetin, begun before surgery, attenuated mechanical allodynia compared to the control group at days 7 and 10 after SNI. On the other hand, established pain was not attenuated in a post-dose group in which quercetin was begun 7 days after SNI. Quercetin inhibited GFAP in the satellite glial cells of the ipsilateral L5 DRG on day 7 compared to the control group. Quercetin suppressed the development of neuropathic pain through a mechanism partly involving the inhibition of satellite glial cells. As its safety is well established, quercetin has great potential for clinical use in pain treatment.

DOI： 10.18926/AMO/56243

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

AIM OF THE RESEARCH: Glutamate transporter-1 (GLT-1; also known as excitatory amino acid transporter 2) plays an important role in the maintenance of glutamate homeostasis in the synaptic cleft. Downregulation of GLT-1 in the spinal cord has been reported in chronic pain models, which suggests that GLT-1 is involved in the development of chronic pain. However, the mechanism by which GLT-1 is downregulated in the spinal cord is still unknown. We hypothesized that norepinephrine is involved in the regulation of GLT-1. The aim of this study was to investigate the effect of norepinephrine on GLT-1 expression in cultured astrocytes. METHODS: This study involved both in vivo and in vitro experiments. We first validated changes in GLT-1 mRNA expression in the spinal cord of rats with spared nerve injury (SNI) using real-time RT-PCR. Next, cultured primary astrocytes from the rat spinal cord were stimulated with norepinephrine, and GLT-1 mRNA was subsequently quantitated. RNB cells, an astrocytic cell line, were also stimulated with norepinephrine and other α-adrenoceptor agonists. RESULTS: SNI resulted in bilateral downregulation of GLT-1 in rat spinal cord. The in vitro study showed that norepinephrine and phenylephrine dose-dependently downregulated GLT-1 in primary astrocytes and RNB cells. Furthermore, the effect of norepinephrine was reversed by an α-adrenoceptor antagonist. CONCLUSION: Norepinephrine downregulates GLT-1 mRNA expression in astrocytes via the α1-adrenoceptor. Our results provide new insight into the mechanisms involved in downregulation of GLT-1 in the chronic pain models.

DOI： 10.1016/j.bbrc.2018.08.137

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Glucose transporter type 1 deficiency syndrome (GLUT1DS) causes central nervous system dysfunction including intractable epilepsy caused by impaired glucose transport to the brain. To prevent convulsions and maintain an energy source for the brain in patients with GLUT1DS, the maintenance of adequate ketone body concentrations, compensation of metabolic acidosis, and reduction of surgical stress are essential. We here report the perioperative management of a child with GLUT1DS.

DOI： 10.1213/XAA.0000000000000727

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Language：Japanese   Publisher：日本臨床麻酔学会  

胸腺腫摘出術術後の抜管時に冠動脈攣縮から心停止に至ったと考えられる1例を経験した。症例は60歳、男性。術前評価で冠動脈器質的異常を認めなかったが、喫煙など複数の冠攣縮危険因子を有していた。腫瘍の浸潤性や術中循環動態の不安定性から、胸骨正中切開、静脈バイパス併用下胸腺腫摘出手術を行った。手術終了後にST上昇先行の心停止を発症したが、蘇生後の心機能回復は良好で、後遺症なく独歩退院した。術後の冠動脈攣縮誘発試験陽性から、心停止の原因は冠攣縮が強く疑われた。高侵襲手術などの手術因子、麻酔覚醒や薬剤投与などの術中因子が合わさり、冠攣縮に伴う心停止に至ったと考えられた。(著者抄録)

DOI： 10.2199/jjsca.38.142

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Aim of investigation: Pulsed radiofrequency (PRF) is a safe and effective approach for treating neuropathic pain. However, the optimal treatment conditions and analgesic mechanisms of PRF remain unclear. The aim of our study was to assess the beneficial and adverse effects of prolonged-duration PRF and the analgesic mechanisms of PRF treatment with neuropathic pain rats. Methods: Male Sprague Dawley rats received L5 spinal nerve ligation (SNL) for developing neuropathic pain. Fourteen days after L5 SNL surgery, they were divided into three groups according to duration of PRF current for 6 minutes, 12 minutes, and none. PRF current was delivered via direct visualization adjacent to the L5 dorsal root ganglion (DRG). Pain behavior was evaluated every week after L5 SNL surgery, until day 28. Seven days after PRF treatment, L5 DRG tissue was harvested to detect levels of activating translation factor 3 (ATF3; a marker of neuronal damage) and hyperpolarization-activated cyclic nucleotide (HCN)-gated cation channels (key factors in neuropathic pain) using quantitative PCR. Results: Before PRF application, withdrawal thresholds were significantly lower than at baseline and did not differ significantly between the three groups. After PRF application, withdrawal thresholds in the PRF6 and PRF12 groups were significantly increased compared to those in the sham group. However, those in the PRF6 and PRF12 groups did not differ significantly. The expression level of ATF3 mRNA in the PRF12 group was significantly higher than that in the sham group (P<0.01), but the expression of HCN1 and HCN2 channels did not differ significantly between the three groups. Conclusion: Prolonged PRF exposure, from 6 to 12 minutes, was not only ineffective but also associated with increased neuronal damage. These findings do not support prolonged PRF exposure as a helpful treatment for neuropathic pain. In this study, the involvement of HCN channels in the antiallodynic effects of PRF was uncertain.

DOI： 10.2147/JPR.S168064

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Language：Japanese   Publisher：医学図書出版(株)  

慢性甲状腺炎(橋本病)は自己免疫性疾患であり、びまん性の甲状腺腫大を呈する。橋本病に対する治療薬中断により、気管切開部の気道狭窄が顕性化した症例を経験したので報告する。症例は57歳男性で、2年前に気管切開の既往があり、4ヵ月前にレボチロキシンの内服により気道狭窄が改善したエピソードがあった。今回は呼吸困難により受診し、頸部CTにて著明な気管狭窄を認め挿管管理となった。気管切開部の狭窄を浮腫や甲状腺腫大が助長させたと考え、利尿による水分管理に加え、レボチロキシンの内服を再開し気道管理を施行した。第6病日に気管狭窄は入室時より改善し抜管に至った。気管切開の既往がある慢性甲状腺炎を有する症例において、甲状腺ホルモン補充中断は甲状腺腫大増悪により気管狭窄を重症化させる危険性が高い。また、侵襲的気道管理を回避するために、甲状腺ホルモンの内服薬開を含めた内科的な集学的治療をまずは考慮すべきである。(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2016359621

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN NEUROSURGICAL SOC  

Perioperative management is critical for positive neurosurgical outcomes. In order to maintain safe and authentic perioperative management, a perioperative management center (PERIO) was introduced to patients of our Neurosurgery Department beginning in June 2014. PERIO involves a multidisciplinary team consisting of anesthesiologists, dentists/dental hygienists/technicians, nurses, physical therapists, pharmacists, and nutritionists. After neurosurgeons decide on the course of surgery, a preoperative evaluation consisting of blood sampling, electrocardiogram, chest X-ray, and lung function test was performed. The patients then visited the PERIO clinic 7-14 days before surgery. One or two days before surgery, the patients without particular issues enter the hospital and receive a mouth cleaning one day before surgery. After surgery, postoperative support involving eating/swallowing evaluation, rehabilitation, and pain control is provided. The differences in duration from admission to surgery, cancellation of surgery, and postoperative complications between PERIO and non-PERIO groups were examined. Eighty-five patients were enrolled in the PERIO group and 131 patients in the non-PERIO group. The duration from admission to surgery was significantly decreased in the PERIO group (3.6 +/- 0.3 days), compared to that in the non-PERIO group (4.7 +/- 0.2 days). There was one cancelled surgery in the PERIO group and six in the non-PERIO group. Postoperative complications and the overall hospital stay did not differ between the two groups. The PERIO system decreased the duration from admission to surgery, and it is useful in providing high-quality medical service, although the system should be improved so as not to increase the burden on medical staff.

DOI： 10.2176/nmc.oa.2016-0085

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Recent studies showed that the administration of dexmedetomidine relieved hyperalgesia in the presence of neuropathic pain. These findings have led to the hypothesis that the local administration of dexmedetomidine is useful for relieving acute inflammatory nociception, such as postoperative pain. Thus, we evaluated the inhibitory effect of locally injected dexmedetomidine on acute inflammatory nociception. Acute inflammatory nociception was induced by an intraplantar injection of 1% carrageenan into the hindpaws of rats, and dexmedetomidine was also injected combined with carrageenan. The paw withdrawal threshold based on von Frey filament stimulation was measured until 12 h after injection. We compared the area under the Lime-curve (AUC) between carrageenan and carrageenan with dexmedetomidine. To clarify that the action of dexmedetomidine was via alpha(2)-adrenoceptors, we evaluated the effect of yohimbine, a selective antagonist of alpha(2)-adrenoceptors, on the anti-nociception of dexmedetomidine. As the results, the intraplantar injection of carrageenan with over 10 mu M dexmedetomidine significantly increased AUC, compared to that with only carrageenan injection. This effect of dexmedetomidine was reversed by the addition of yohimbine to carrageenan and dexmedetomidine. These results demonstrated that the locally injected dexmedetomidine was effective against carrageenan-induced inflammatory nociception via alpha(2)-adrenoceptors. The findings suggest that the local injection of dexmedetomidine is useful for relieving local acute inflammatory nociception. (C) 2015 Elsevier B.V. All rights reserved,

DOI： 10.1016/j.ejphar.2015.06.054

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：DOVE MEDICAL PRESS LTD  

Metastatic bone cancer causes severe pain, but current treatments often provide insufficient pain relief. One of the reasons is that mechanisms underlying bone cancer pain are not solved completely. Our previous studies have shown that brain-derived neurotrophic factor (BDNF), known as a member of the neurotrophic family, is an important molecule in the pathological pain state in some pain models. We hypothesized that expression changes of BDNF may be one of the factors related to bone cancer pain; in this study, we investigated changes of BDNF expression in dorsal root ganglia in a rat bone cancer pain model. As we expected, BDNF mRNA (messenger ribonucleic acid) and protein were significantly increased in L3 dorsal root ganglia after intra-tibial inoculation of MRMT-1 rat breast cancer cells. Among the eleven splice-variants of BDNF mRNA, exon 1-9 variant increased predominantly. Interestingly, the up-regulation of BDNF is localized in small neurons (mostly nociceptive neurons) but not in medium or large neurons (non-nociceptive neurons). Further, expression of nerve growth factor (NGF), which is known as a specific promoter of BDNF exon 1-9 variant, was significantly increased in tibial bone marrow. Our findings suggest that BDNF is a key molecule in bone cancer pain, and NGF-BDNF cascade possibly develops bone cancer pain.

DOI： 10.2147/JPR.S63527

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：DOVE MEDICAL PRESS LTD  

It is generally known that peripheral nerve injury causes changes in expression of some growth factors in the dorsal root ganglion. Altered expression of ErbB receptors, a well-known growth factor in somatic cells, reportedly follows peripheral nerve injury in the spinal dorsal horn; however, it remains unknown whether the expression of these receptors is altered in the dorsal root ganglion after nerve injury. Therefore, this study examined the gene expression profiles of ErbB receptors in bilateral lumbar (L) 4/L5 dorsal root ganglia, using L5-selective spinal nerve ligation in model rats as a peripheral nerve injury model. The expression of ErbB2 and ErbB3 was observed in the dorsal root ganglia of the mature rat, despite ErbB1 and ErbB4 showing only subtle expression. We also demonstrated that peripheral nerve injury induced significant increases in ErbB2 and ErbB3 in the ipsilateral dorsal root ganglion as compared with uninjured nerve. Expression changes in ErbB receptors appear to play important roles in nerve injury and subsequent nerve regeneration.

DOI： 10.2147/JPR.S40967

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Perioperative beta-blocker administration has recently been recommended for patients undergoing cardiac or other surgery due to the beneficial cardiovascular effects of these agents. In addition, some studies have reported that perioperatively administered beta-blockers also have analgesic effects. In this study, to investigate the antinociceptive effects and the analgesic profile of landiolol, we examined the effects of intrathecal landiolol administration on nociceptive pain behavior and c-fos mRNA expression (a neural marker of pain) in the spinal cord using a rat formalin model. We found that pain-related behavior was inhibited by intrathecal landiolol administration. Moreover, the increase in c-fos mRNA expression on the formalin-injected side was less pronounced in rats administered landiolol than in saline administered controls. Thus, intrathecal administration of landiolol exhibited antinociceptive effects. Further investigation of the antinociceptive mechanism of landiolol is required.

DOI： 10.18926/AMO/48569

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Sigma1 receptors (Sigma1R) are intracellular chaperone proteins that bind psychotropic drugs and also clinically used drugs such as ketamine and haloperidol. Co-expression of the Sigma1R has been reported to enhance the sensitivity of several voltage-gated ion channels to Sigma1R ligands. Kv1.3 is the predominant voltage-gated potassium channel expressed in T lymphocytes with a documented role in immune activation. To gain a better understanding of Sigrna1R modulation of Kv ion channels, we investigated the effects of Sigma1R co-expression on Kv1.3 physiology and pharmacology in ion channels expressed in Xenopus oocytes. We also explored the protein domains of Kv1.3 necessary for protein:protein interaction between Kv1.3 and Sigma1R through co-immunoprecipitation studies. Slowly inactivating outward-going currents consistent with Kv1.3 expression were elicited on step depolarizations. The current characterized by E-rev, V-1/2, and slope factor remained unchanged when co-expressed with Sigma1R. Analysis of inactivation time constant revealed a faster Kv1.3 current decay when co-expressed with Sigma1R. However the sensitivity to Sigma1R ligands remained unaltered when co-expressed with the Sigma1R in contrast to the previously reported modulation of ligand sensitivity in closely related Kv1.4 and Kv1.5 voltage gated potassium channels. Co-immunoprecipitation assays of various Kv1.3 truncation constructs indicated that the transmembrane domain of the Kv1.3 protein was responsible for the protein:protein interaction with the Sigma1R. Sigma1R likely interacts with different domains of Kv ion channel family proteins resulting in distinct modulation of different channels. (C) 2012 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.brainres.2012.02.070

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Brain-derived neurotrophic factor (BDNF) plays a key role in the development of pathological pain. Although it is known that nerve growth factor (NGF) induces BDNF mRNA through extracellular signal-regulated kinases (ERK), whether ERK1/2 or ERK5, two closely related members of the ERK family, mediate this signal is still unclear because classical MEK inhibitors block both pathways. We studied the involvement of ERK-signaling in NGF induction of BDNF in PC12 cells, cultured dorsal root ganglia neurons, and in rats subjected to neuropathic pain models using ERK1/2- and ERK5-specific tools. Selective activation of ERK1/2 upregulated BDNF mRNA in PC12 cells, whereas selective ERK5 activation did not. AZD6244, a potent selective inhibitor of ERK1/2 activation, blocked NGF induction of BDNF mRNA in vitro suggesting that NGF induction of BDNF is mediated by ERK1/2. siRNA experiments indicated that both ERK1 or ERK2 can signal suggesting that both pathways must be blocked to prevent NGF-induced increase in BDNF mRNA. I.p. injection of AZD6244 prevented the development of pain in rats subjected to the chronic constriction injury and reversed already established pain in the spared nerve injury model. Immunohistochemical studies showed decreased phospho-ERK1/2-immunoreactivity in dorsal root ganglia and BDNF immunoreactivity in ipsilateral spinal dorsal horn in the drug-treated rats. Our results suggest the possible use of AZD6244, already in human clinical trials as an anticancer agent, for the treatment of pathological pain. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.neuroscience.2012.01.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The mechanism underlying neuropathic pain is still largely unclear. Recently, much attention has been focused on the role of brain-derived neurotrophic factor (BDNF) as a neuromodulator in the spinal cord. We previously reported that the expression of Bdnf exon I mRNA was remarkably up-regulated in the dorsal root ganglion (DRG) neurons with the rat L5 spinal nerve ligation (SNL) model. In the present study, we investigated whether neuropathic pain response would be reduced by the inhibition of the Bdnf exon I in the rat SNL model. We identified the promoter region of exon I and synthesized the decoy ODNs targeting the region. Reverse transcription-polymerase chain reaction analysis confirmed that the decoy ODN treatment reduced SNL-induced Bdnf exon I mRNA up-regulation in ipsilateral L4 and L5 DRGs. Furthermore, post-treatment with the decoy ODNs significantly attenuated SNL-induced tactile allodynia. This study suggested that decoy ODNs targeting the Bdnf exon I might provide a novel analgesic strategy for the treatment of neuropathic pain. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2011.03.137

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

We investigated changes in pain behavior after injection of acetic acid in the hindpaws of rats with L5 spinal nerve ligation (SNL)-induced neuropathy. We also examined immunoreactivity for acid-sensing ion channel 3 (ASIC3) in the dorsal root ganglion (DRG) of rats with L5 SNL. Two weeks after SNL, the withdrawal threshold to a mechanical stimulus was significantly lower in the SNL group than in the sham-operated group (n=9 per group, P&lt;0.01). After acetic acid injection, spontaneous pain responses in the SNL group were significantly increased compared to those in the sham-operated group (n = 5, P &lt; 0.05). L5 SNL significantly increased the proportion of total ASIC3-immunoreactive (ir) neurons in the ipsilateral L4 DRG compared to that in sham-operated rats (n = 4, P &lt; 0.01). Analysis of cell size showed that the proportion of large (&gt; 1200 mm(2)) ASIC3-ir neurons in the ipsilateral L4 DRG significantly increased after L5 SNL (P&lt;0.05). In the ipsilateral L5 DRG, the proportion of ASIC3-ir neurons was not significantly affected by treatment. However, L5 SNL significantly increased (P&lt;0.01) the proportion of small (&lt;1200 mm(2)) ASIC3-ir neurons and significantly decreased (P&lt;0.01) the proportion of large ASIC3-ir neurons compared to proportions in sham-operated animals. These findings suggest that ASIC3 is associated with hyperalgesia in response to a chemical stimulus in the L5 SNL rat model. (C) 2008 Published by Elsevier B.V.

DOI： 10.1016/j.brainres.2008.03.040

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Brain-derived neurotrophic factor (BDNF) expression changes in the dorsal root ganglion (DRG) and spinal cord in some pain models. Recently, rat BDNF transcripts containing novel 5' untranslated exons were identified and characterized, and a new numbering system for rat BDNF exons was introduced. We examined the expression profiles of these novel BDNF transcripts in bilateral L4/5 DRGs in an L5-selective spinal nerve ligation (SSNL) model and bilateral L5 DRGs in a complete Freund's adjuvant (CFA) model of rats. L5SSNL increased significantly (P&lt;0.05) the expression of total BDNF mRNA and exon I, IIA, IIB, IIC, III, IV, VI, and IXA transcripts in ipsilateral L4 DRG. Although expression of total BDNF mRNA remained unchanged in ipsilateral L5 DRG in the L5SSNL model, expression of exon I transcript increased significantly (P&lt;0.05) and that of exon IV transcript decreased significantly (P&lt;0.05). The expression profiles of the variant exons in ipsilateral L4 DRG of the L5SSNL model were quite similar to those in ipsilateral DRG of the CFA model, and exon I transcript was the most common BDNF mRNA in these DRGs. Although L5SSNL increased significantly (P&lt;0.05) the expression of total BDNF mRNA and exon IIC and IXA transcripts in the contralateral L4/5 DRGs, CFA treatment did not alter the expression of total BDNF mRNA or specific transcripts in the contralateral DRGs. These findings suggest that exon I plays an important role in the increase in BDNF expression in ipsilateral DRGs regardless of condition. (C) 2008 Published by Elsevier B.V.

DOI： 10.1016/j.brainres.2007.12.004

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Expression of brain-derived neurotrophic factor (BDNF) mRNA is increased in the dorsal root ganglion (DRG) in response to peripheral inflammation. Nerve growth factor (NGF) from inflammatory tissue is thought to induce expression of BDNF. Recently, it was reported that the BDNF gene has eight non-coding exons that are transcribed independently into several splice variants. Expression of these splice variants in DRG neurons stimulated with NGF has not been studied. We examined changes in expression of BDNF splice variants in a rat model of peripheral inflammation and in cultured DRG neurons exposed to NGF. Total BDNF mRNA was increased by inflammation in vivo and by NGF in uitro. Among all splice variants, exon 1-9 showed the greatest increase in expression in both experiments. Our results indicate that exon 1-9 contributes to changes in total BDNF levels and may play an important role in the acute response of DRG to NGF. (c) 2007 Published by Elsevier Inc.

DOI： 10.1017/j.bbrc.2007.08.022

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

BACKGROUND: The status of neuropathic pain alters the responsiveness to formalin injection in rats. However, the mechanism by which this alteration occurs is unknown.
METHODS: We used immunocytochemistry to examine the expression of brain-derived neurotrophic factor (BDNF) and calcitonin gene-related peptide (CGRP) in the spinal cord of rats with L5 spinal nerve ligation (SNL)-induced neuropathy, and investigated the expression of c-Fos in the spinal cord after injection of formalin in the hindpaw of rats with SNL.
RESULTS: Four weeks after SNL, the withdrawal threshold was significantly lower in the SNL group than in the sham-operated (sham) group (n = 12 per group, P &lt; 0.05). In the SNL group, expression of BDNF in the L4 (P &lt; 0.05) and L5 (P &lt; 0.01) superficial dorsal horn was significantly decreased compared to that in the sham group. CGRP protein in the L5 but not in the L4, dorsal horn was significantly decreased compared to that in the sham group (P &lt; 0.01). After formalin injection, spontaneous pain responses in the SNL group were significantly decreased compared to those in the sham group (P &lt; 0.05). Immunolabeling for c-Fos was significantly decreased in the L4 and L5 dorsal horn in the SNL group (P &lt; 0.01).
CONCLUSION: Our examination of c-Fos distribution indicates that decreased neuronal activity in the spinal cord in response to inflammatory pain may be important for altering the perception of acute pain. Decreased BDNF expression in response to SNL-induced neuropathy may be involved in this alteration.

DOI： 10.1213/01.ane.0000258762.22607.15

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Total pages：680p   Language：Japanese

CiNii Books

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Total pages：357p   Language：Japanese

CiNii Books

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Total pages：326p   Language：Japanese

CiNii Books

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Total pages：p289-556   Language：Japanese

CiNii Books

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：日本臨床麻酔学会  

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Language：Japanese   Publisher：(株)メディカル・サイエンス・インターナショナル  

＜文献概要＞岡山大学病院(以下,当院)は,2008年に周術期管理センターperioperative management center(PERIO)を開設し,多職種連携による周術期管理を目指してきた。2018年には10周年を迎え,2020年時点で12年目である。本稿では,これまでのPERIOの歴史を振り返りながら,これからの周術期管理について考えてみたい。

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Language：Japanese   Publisher：日本老年麻酔学会  

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J-GLOBAL

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Language：Japanese   Publisher：日本臨床麻酔学会  

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Language：Japanese   Publisher：日本臨床麻酔学会  

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Language：Japanese   Publisher：日本臨床麻酔学会  

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Language：Japanese   Publisher：日本臨床麻酔学会  

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Language：Japanese   Publisher：(一社)日本ペインクリニック学会  

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Language：Japanese   Publisher：日本疼痛学会  

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Language：Japanese   Publisher：(株)総合医学社  

＜point＞患者の状態、薬液、投与経路に応じて各項目を設定する。初期投与は効果を評価しながら行う。高齢者・重症患者では少量から始める。開始後も定期的に回診し、副作用対策、設定の見直しによって患者の満足度の高い鎮痛効果を目指す。(著者抄録)

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Language：Japanese   Publisher：日本疼痛学会  

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Language：Japanese   Publisher：日本疼痛学会  

J-GLOBAL

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Language：Japanese   Publisher：克誠堂出版(株)  

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Event date： 2022.11.11 - 2022.11.12

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2022.11.11 - 2022.11.12

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Event date： 2022.10.20 - 2022.10.22

Presentation type：Symposium, workshop panel (nominated)  

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Event date： 2022.9.2 - 2022.10.3

Language：Japanese   Presentation type：Poster presentation  

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Event date： 2022.9.2 - 2022.10.3

Language：Japanese   Presentation type：Poster presentation  

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Event date： 2022.6.16 - 2022.6.18

Language：English   Presentation type：Poster presentation  

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Event date： 2022.6.16 - 2022.6.18

Language：English   Presentation type：Poster presentation  

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Event date： 2020.3.6

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2020.2.8 - 2020.2.9

Language：Japanese   Presentation type：Oral presentation (general)  

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Language：Japanese   Presentation type：Oral presentation (general)  

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Language：Japanese   Presentation type：Oral presentation (general)  

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