Publications by authors named "Hitoshi Niwa"

172 Publications

Isoflurane induces Art2-Rsp5-dependent endocytosis of Bap2 in yeast.

FEBS Open Bio 2021 Sep 18. Epub 2021 Sep 18.

Center of Frontier Oral Science, Graduate School of Dentistry, Osaka University, Suita, Japan.

Although general anesthesia is indispensable during modern surgical procedures, the mechanism by which inhalation anesthetics act on the synaptic membrane at the molecular and cellular level is largely unknown. In this study, we used yeast cells to examine the effect of isoflurane, an inhalation anesthetic, on membrane proteins. Bap2, an amino acid transporter localized on the plasma membrane, was endocytosed when yeast cells were treated with isoflurane. Depletion of RSP5, an E3 ligase, prevented this endocytosis and Bap2 was ubiquitinated in response to isoflurane, indicating an ubiquitin-dependent process. Screening all the Rsp5 binding adaptors showed that Art2 plays a central role in this process. These results suggest that isoflurane affects Bap2 via an Art2-Rsp5-dependent ubiquitination system.
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http://dx.doi.org/10.1002/2211-5463.13302DOI Listing
September 2021

Anti-calcitonin gene-related peptide antibody attenuates orofacial mechanical and heat hypersensitivities induced by infraorbital nerve injury.

Biochem Biophys Res Commun 2021 Sep 8;569:147-153. Epub 2021 Jul 8.

Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan. Electronic address:

Currently, limited information regarding the role of calcitonin gene-related peptide (CGRP) in neuropathic pain is available. Intracerebroventricular administrations of an anti-CGRP antibody were performed in rats with infraorbital nerve ligation. Anti-CGRP antibody administration attenuated mechanical and heat hypersensitivities induced by nerve ligation and decreased the phosphorylated extracellular signal-regulated kinase expression levels in the trigeminal spinal subnucleus caudalis (Vc) following mechanical or heat stimulation. An increased CGRP immunoreactivity in the Vc appeared after nerve ligation. A decreased CGRP immunoreactivity resulted from anti-CGRP antibody administration. Our findings suggest that anti-CGRP antibody administration attenuates the symptoms of trigeminal neuropathic pain by acting on CGRP in the Vc.
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http://dx.doi.org/10.1016/j.bbrc.2021.07.001DOI Listing
September 2021

Meiosis-specific ZFP541 repressor complex promotes developmental progression of meiotic prophase towards completion during mouse spermatogenesis.

Nat Commun 2021 06 1;12(1):3184. Epub 2021 Jun 1.

Department of Chromosome Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto, Japan.

During spermatogenesis, meiosis is accompanied by a robust alteration in gene expression and chromatin status. However, it remains elusive how the meiotic transcriptional program is established to ensure completion of meiotic prophase. Here, we identify a protein complex that consists of germ-cell-specific zinc-finger protein ZFP541 and its interactor KCTD19 as the key transcriptional regulators in mouse meiotic prophase progression. Our genetic study shows that ZFP541 and KCTD19 are co-expressed from pachytene onward and play an essential role in the completion of the meiotic prophase program in the testis. Furthermore, our ChIP-seq and transcriptome analyses identify that ZFP541 binds to and suppresses a broad range of genes whose function is associated with biological processes of transcriptional regulation and covalent chromatin modification. The present study demonstrates that a germ-cell specific complex that contains ZFP541 and KCTD19 promotes the progression of meiotic prophase towards completion in male mice, and triggers the reconstruction of the transcriptional network and chromatin organization leading to post-meiotic development.
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http://dx.doi.org/10.1038/s41467-021-23378-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169937PMC
June 2021

Generation of Mitochondrial Toxin Rodent Models of Parkinson's Disease Using 6-OHDA , MPTP , and Rotenone.

Methods Mol Biol 2021 ;2322:95-110

Department of Dental Anesthesia, Osaka University Graduate School of Dentistry, Osaka, Japan.

Several animal models are employed to discover novel treatments for the symptoms of Parkinson's disease (PD). PD models can be divided into two models: neurotoxin models and genetic models. Among neurotoxins to produce PD models, 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and rotenone, which inhibit the mitochondrial complex I, are widely used. Animal models of PD using these neurotoxins are also known as mitochondrial toxin models. Here this chapter describes the preparation of these mitochondrial toxin models.
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http://dx.doi.org/10.1007/978-1-0716-1495-2_10DOI Listing
August 2021

Swallowing ability and intra-oral water-retaining ability during moderate propofol sedation in healthy human volunteers: A prospective observational study.

Eur J Anaesthesiol 2021 11;38(11):1138-1147

From the Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan (HH, CY, HN); Kobe Dental Center, Kobe, Japan (ET).

Background: The cough reflex or aspiration under monitored anaesthesia care might be associated with sedative-induced changes in swallowing and intra-oral water-retaining abilities.

Objectives: To investigate the effects of moderate propofol sedation on swallowing and intra-oral water-retaining ability.

Design: Prospective observational study.

Setting: Single tertiary care centre during 2017.

Participants: A total of 13 healthy adult volunteers.

Intervention: Volunteers in the supine position were asked to retain 10 ml of orally injected water for 5 min. After 5 minutes or when the water was spontaneously swallowed, the retention time and residual intra-oral water volume were measured. Subjects then voluntarily swallowed a further 10 ml of injected water and the residual water volume was measured. This whole process was repeated under sedation with propofol at effect-site concentrations of 0.5, 1.0 and 1.5 μg ml-1.

Main Outcome Measures: The primary outcome was the estimated volume swallowed (swallowing volume); the secondary outcome was water retention time.

Results: Median water retention time decreased from 300 to 11 s (P < 0.001), and greater spontaneous swallowing was induced with increased propofol effect-site concentrations measuring up to 1.5 μg ml-1 (P < 0.001). The median of the estimated swallowing volumes with voluntary swallowing while awake and with all three concentrations of propofol were 9.5, 9.6, 9.6 and 9.4 ml, respectively (P = 0.805); more water remained after spontaneous swallowing than after voluntary swallowing at all concentrations. Differences in mean estimated swallowing volumes between voluntary and spontaneous swallowing were 3.4 ml (95% CI, 0.9 to 6.0, P = 0.016) for 0.5 μg ml-1, 4.1 ml (95% CI, 1.8 to 6.3, P = 0.002) for 1.0 μg ml-1 and 5.1 ml (95% CI, 3.4 to 6.8, P < 0.001) for 1.5 μg ml-1.

Conclusions: Moderate propofol sedation decreases water-retaining ability but has no effect on voluntary swallowing. Ensuring that patients can respond under sedation may effectively prevent the unexpected cough reflex and aspiration by enabling occasional voluntary swallowing.

Trial Registration: UMIN Clinical Trials Registry identifier: UMIN000027517.
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http://dx.doi.org/10.1097/EJA.0000000000001523DOI Listing
November 2021

Increased expression of Netrin-4 is associated with allodynia in a trigeminal neuropathic pain model rats by infraorbital nerve injury.

PLoS One 2021 29;16(4):e0251013. Epub 2021 Apr 29.

Department of Molecular Neuroscience, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Neuropathic pain refers to pain caused by lesions or diseases of the somatosensory nervous system that is characteristically different from nociceptive pain. Moreover, neuropathic pain occurs in the maxillofacial region due to various factors and is treated using tricyclic antidepressants and nerve block therapy; however, some cases do not fully recover. Netrin is a secreted protein crucially involved in neural circuit formation during development, including cell migration, cell death, neurite formation, and synapse formation. Recent studies show Netrin-4 expressed in the dorsal horn of the spinal cord is associated with chronic pain. Here we found involvement of Netrin-4 in neuropathic pain in the maxillofacial region. Netrin-4, along with one of its receptors, Unc5B, are expressed in the caudal subnucleus of the trigeminal spinal tract nucleus. Inhibition of its binding by anti-Netrin-4 antibodies not only shows a behavioral analgesic effect but also neuronal activity suppression. There was increased Netrin-4 expression at 14 days after infraorbital nerve injury. Our findings suggest that Netrin-4 induced by peripheral nerve injury causes neuropathic pain via Unc5B.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251013PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084253PMC
September 2021

Clinical Use of Preformed Microcuff® Pediatric Endotracheal Tubes in Japan.

Anesth Prog 2021 03;68(1):45-46

Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, Suita, Japan.

Preformed cuffed oral endotracheal tubes are widely used to intubate children undergoing oral surgery. To evaluate the efficacy and safety of oral Ring-Adair-Elwyn (RAE) Microcuff® pediatric endotracheal tubes, we retrospectively investigated the endotracheal tube exchange rate and associated complications in Japanese children younger than 2 years of age undergoing cheiloplasty or palatoplasty. The exchange rate was 3.5%, and although unplanned extubations occurred in 2 patients, no severe complications were observed. Our results suggest that oral RAE Microcuff® tubes are effective and safe for intubating Japanese children younger than 2 years of age, with a low tube exchange rate and minor complications.
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http://dx.doi.org/10.2344/anpr-67-04-03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033575PMC
March 2021

Inhibition of repulsive guidance molecule-a protects dopaminergic neurons in a mouse model of Parkinson's disease.

Cell Death Dis 2021 02 15;12(2):181. Epub 2021 Feb 15.

Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Repulsive guidance molecule-a (RGMa), a glycosylphosphatidylinositol-anchored membrane protein, has diverse functions in axon guidance, cell patterning, and cell survival. Inhibition of RGMa attenuates pathological dysfunction in animal models of central nervous system (CNS) diseases including spinal cord injury, multiple sclerosis, and neuromyelitis optica. Here, we examined whether antibody-based inhibition of RGMa had therapeutic effects in a mouse model of Parkinson's disease (PD). We treated mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and found increased RGMa expression in the substantia nigra (SN). Intraventricular, as well as intravenous, administration of anti-RGMa antibodies reduced the loss of tyrosine hydroxylase (TH)-positive neurons and accumulation of Iba1-positive microglia/macrophages in the SN of MPTP-treated mice. Selective expression of RGMa in TH-positive neurons in the SN-induced neuronal loss/degeneration and inflammation, resulting in a progressive movement disorder. The pathogenic effects of RGMa overexpression were attenuated by treatment with minocycline, which inhibits microglia and macrophage activation. Increased RGMa expression upregulated pro-inflammatory cytokine expression in microglia. Our observations suggest that the upregulation of RGMa is associated with the PD pathology; furthermore, inhibitory RGMa antibodies are a potential therapeutic option.
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http://dx.doi.org/10.1038/s41419-021-03469-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884441PMC
February 2021

Frequency of the requirement of inappropriate uncuffed tracheal tube size for pediatric patients: a retrospective observational analysis.

BMC Anesthesiol 2021 02 3;21(1):34. Epub 2021 Feb 3.

Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, 1-8 Yamada-Oka, Suita, Osaka, 565-0871, Japan.

Background: The insertion of inappropriately sized uncuffed endotracheal tubes (ETTs) with a tight seal or presence of air leakage may be necessary in children. This study aimed to analyze the frequency of the requirement of inappropriately sized uncuffed ETT insertion, air leakage after the ETT was replaced with one of a larger size, and factors associated with air leakage after ETT replacement.

Methods: Patients under 2 years of age who underwent oral surgery under general anesthesia with uncuffed ETTs between December 2013 and May 2015 were enrolled. The ETT size was selected at the discretion of the attending anesthesiologists. A leak test was performed after intubation. The ETT was replaced when considered necessary. Data regarding the leak pressure (P) and inspiratory and expiratory tidal volumes were extracted from anesthesia records. We considered a P of 10 < P ≤ 30 cmHO to be appropriate. The frequencies of the requirement of inappropriately sized ETTs, absence of leakage after ETT replacement, ETT size difference, and leak rate were calculated. A logistic regression was performed, with P, leak rate, and size difference included as explanatory variables and presence of leakage after replacement as the outcome variable.

Results: Out of the 156 patients enrolled, 109 underwent ETT replacement, with the requirement of inappropriately sized ETTs being observed in 25 patients (23%). ETT replacement was performed in patients with P ≤ 10 cmHO; leakage was absent after replacement (P < 30 cmHO) in 52% of patients (25/48). In the multivariate logistic model, the leak rate before ETT replacement was significantly associated with the presence of leakage after replacement (p = 0.021).

Conclusions: Inappropriately sized ETTs were inserted in approximately 23% of the patients. The leak rate may be useful to guide ETT replacement.
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http://dx.doi.org/10.1186/s12871-021-01258-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856756PMC
February 2021

Molecular detection of maturation stages in the developing kidney.

Dev Biol 2021 02 14;470:62-73. Epub 2020 Nov 14.

Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan. Electronic address:

Recent advances in stem cell biology have enabled the generation of kidney organoids in vitro, and further maturation of these organoids is observed after experimental transplantation. However, the current organoids remain immature and their precise maturation stages are difficult to determine because of limited information on developmental stage-dependent gene expressions in the kidney in vivo. To establish relevant molecular coordinates, we performed single-cell RNA sequencing (scRNA-seq) on developing kidneys at different stages in the mouse. By selecting genes that exhibited upregulation at birth compared with embryonic day 15.5 as well as cell lineage-specific expression, we generated gene lists correlated with developmental stages in individual cell lineages. Application of these lists to transplanted embryonic kidneys revealed that most cell types, other than the collecting ducts, exhibited similar maturation to kidneys at the neonatal stage in vivo, revealing non-synchronous maturation across the cell lineages. Thus, our scRNA-seq data can serve as useful molecular coordinates to assess the maturation of developing kidneys and eventually of kidney organoids.
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http://dx.doi.org/10.1016/j.ydbio.2020.11.002DOI Listing
February 2021

MEAF6 is essential for cell proliferation and plays a role in the assembly of KAT7 complexes.

Exp Cell Res 2020 11 9;396(1):112279. Epub 2020 Sep 9.

Department of Pluripotent Stem Cell Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan; Liaison Laboratory Research Promotion Center, IMEG, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan. Electronic address:

Myst family genes encode lysine acetyltransferases that mainly mediate histone acetylation to control transcription, DNA replication and DNA damage response. They form tetrameric complexes with PHD-finger proteins (Brpfs or Jades) and small non-catalytic subunits Ing4/5 and Meaf6. Although all the components of the complex are well-conserved from yeast to mammals, the function of Meaf6 and its homologs has not been elucidated in any species. Here we revealed the role of Meaf6 utilizing inducible Meaf6 KO ES cells. By elimination of Meaf6, proliferation ceased although histone acetylations were largely unaffected. In the absence of Meaf6, one of the Myst family members Myst2/Kat7 increased the ability to interact with PHD-finger proteins. This study is the first indication of the function of Meaf6, which shows it is not essential for HAT activity but modulates the assembly of the Kat7 complex.
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http://dx.doi.org/10.1016/j.yexcr.2020.112279DOI Listing
November 2020

Distinct transcriptional programs of SOX2 in different types of small cell lung cancers.

Lab Invest 2020 12 14;100(12):1575-1588. Epub 2020 Aug 14.

Department of Pathology and Experimental Medicine, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan.

SOX2 is recognized as an oncogene in human small cell lung cancer (SCLC), which is an aggressive neuroendocrine (NE) tumor. However, the role of SOX2 in SCLC is not completely understood, and strategies to selectively target SOX2 in SCLC cells remain elusive. Here, we show, using next-generation sequencing, that SOX2 expressed in the ASCL1-high SCLC (SCLC-A) subtype cell line is dependent on ASCL1, which is a lineage-specific transcriptional factor, and is involved in NE differentiation and tumorigenesis. ASCL1 recruits SOX2, which promotes INSM1 and WNT11 expression. Immunohistochemical studies revealed that SCLC tissue samples expressed SOX2, ASCL1, and INSM1 in 18 out of the 30 cases (60%). Contrary to the ASCL1-SOX2 signaling axis controlling SCLC biology in the SCLC-A subtype, SOX2 targets distinct genes such as those related to the Hippo pathway in the ASCL1-negative, YAP1-high SCLC (SCLC-Y) subtype. Although SOX2 knockdown experiments suppressed NE differentiation and cell proliferation in the SCLC-A subtype, they did not sufficiently impair the growth of the SCLC-Y subtype cell lines in vitro and ex vivo. The present results support the importance of the ASCL1-SOX2 axis as a main subtype of SCLC, and suggest the therapeutic potential of targeting the ASCL1-SOX2 axis.
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http://dx.doi.org/10.1038/s41374-020-00479-0DOI Listing
December 2020

Establishment of bone marrow-derived M-CSF receptor-dependent self-renewing macrophages.

Cell Death Discov 2020 23;6:63. Epub 2020 Jul 23.

Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811 Japan.

Recent studies have revealed that tissue macrophages are derived from yolk sac precursors or fetal liver monocytes, in addition to bone marrow monocytes. The relative contribution of these cells to the tissue macrophage pool is not fully understood, but embryo-derived cells are supposed to be more important because of their capacity to self-renew. Here, we show the presence of adult bone marrow-derived macrophages that retain self-renewing capacity. The self-renewing macrophages were readily obtained by long-term culture of mouse bone marrow cells with macrophage colony-stimulating factor (M-CSF), a key cytokine for macrophage development. They were non-tumorigenic and proliferated in the presence of M-CSF in unlimited numbers. Despite several differences from non-proliferating macrophages, they retained many features of cells of the monocytic lineage, including the differentiation into dendritic cells or osteoclasts. Among the transcription factors involved in the self-renewal of embryonic stem cells, Krüppel-like factor 2 (KLF2) was strongly upregulated upon M-CSF stimulation in the self-renewing macrophages, which was accompanied by the downregulation of MafB, a transcription factor that suppresses KLF2 expression. Indeed, knockdown of KLF2 led to cell cycle arrest and diminished cell proliferation in the self-renewing macrophages. Our new cell model would be useful to unravel differences in phenotype, function, and molecular mechanism of proliferation among self-renewing macrophages with different origins.
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http://dx.doi.org/10.1038/s41420-020-00300-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378060PMC
July 2020

Anesthetic Management of a Patient With a Vagal Nerve Stimulator.

Anesth Prog 2020 ;67(1):16-22

Department of Dental Anesthesiology, Field of Oral and Maxillofacial Rehabilitation, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Vagal nerve stimulation (VNS) is an established adjunctive treatment for patients with refractory epilepsy. VNS is effective in many cases, but few patients achieve complete elimination of seizures. Furthermore, VNS can cause respiratory complications, such as obstructive sleep apnea. This report describes the successful anesthetic management of a 28-year-old woman with a VNS device who underwent dental treatment under general anesthesia. She was morbidly obese and had undergone placement of a VNS device secondary to drug-resistant epilepsy 2 years prior but continued to experience daily epileptic seizures. Because of concerns about the risk of perioperative epileptic seizures and apneic events, use of the dedicated VNS device magnet was planned if such complications occurred. Total intravenous anesthesia was induced with propofol and remifentanil and a bispectral index sensor was used to help monitor brain wave activity for evidence of seizures along with the depth of anesthesia. Postoperatively, the patient received positional therapy and supplemental oxygen while being closely monitored in recovery. The anesthetic course was completed uneventfully without need of the VNS magnet. A thorough understanding of the mechanics of a VNS device, including proper use of the VNS magnet, is critical for an anesthesiologist during the perioperative period.
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http://dx.doi.org/10.2344/anpr-66-03-02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083113PMC
November 2020

An Avulsed Tooth Detected Prior to Insertion of a Laryngeal Mask Airway.

Anesth Prog 2020 ;67(1):35-38

Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, Suita, Japan.

This case report describes the importance of inspecting the hypopharynx via direct laryngoscopy prior to laryngeal mask airway (LMA) insertion during induction of general anesthesia for dental patients with special needs. A 51-year-old man with cerebral palsy underwent induction of general anesthesia for dental extractions and subsequently was noted to be missing a tooth. Prompt inspection of the airway via direct laryngoscopy revealed the tooth resting within the pharynx, which was subsequently retrieved, prior to insertion of the LMA. Visual inspection of the oropharynx and hypopharynx by laryngoscopy prior to LMA insertion can be useful in preventing accidental aspiration and ingestion of foreign bodies, particularly with certain high-risk patients. Use of laryngoscopy should also be considered if an object is lost or possibly impinging upon the airway.
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http://dx.doi.org/10.2344/anpr-66-04-01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083122PMC
November 2020

Dopaminergic Modulation of Orofacial Mechanical Hypersensitivity Induced by Infraorbital Nerve Injury.

Int J Mol Sci 2020 Mar 12;21(6). Epub 2020 Mar 12.

Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan.

While the descending dopaminergic control system is not fully understood, it is reported that the hypothalamic A11 nucleus is its principle source. To better understand the impact of this system, particularly the A11 nucleus, on neuropathic pain, we created a chronic constriction injury model of the infraorbital nerve (ION-CCI) in rats. ION-CCI rats received intraperitoneal administrations of quinpirole (a dopamine D2 receptor agonist). ION-CCI rats received microinjections of quinpirole, muscimol [a gamma-aminobutyric acid type A (GABA) receptor agonist], or neurotoxin 6-hydroxydopamine (6-OHDA) into the A11 nucleus. A von Frey filament was used as a mechanical stimulus on the maxillary whisker pad skin; behavioral and immunohistochemical responses to the stimulation were assessed. After intraperitoneal administration of quinpirole and microinjection of quinpirole or muscimol, ION-CCI rats showed an increase in head-withdrawal thresholds and a decrease in the number of phosphorylated extracellular signal-regulated kinase (pERK) immunoreactive (pERK-IR) cells in the superficial layers of the trigeminal spinal subnucleus caudalis (Vc). Following 6-OHDA microinjection, ION-CCI rats showed a decrease in head-withdrawal thresholds and an increase in the number of pERK-IR cells in the Vc. Our findings suggest the descending dopaminergic control system is involved in the modulation of trigeminal neuropathic pain.
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http://dx.doi.org/10.3390/ijms21061945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139594PMC
March 2020

MEIOSIN Directs the Switch from Mitosis to Meiosis in Mammalian Germ Cells.

Dev Cell 2020 02 6;52(4):429-445.e10. Epub 2020 Feb 6.

Department of Pluripotent Stem Cell Biology, IMEG, Kumamoto University, Kumamoto 860-0811, Japan.

The mechanisms regulating meiotic initiation in mammals are enigmatic. It is known that retinoic acid (RA) signaling plays a pivotal role during meiotic initiation. STRA8, which is expressed in response to RA, is thought to be a key factor promoting meiotic initiation. However, the specific role of STRA8 in meiotic initiation has remained elusive. Here, we identified MEIOSIN as a germ-cell-specific factor that associates with STRA8. MEIOSIN, like STRA8, is expressed in response to RA and plays an essential role in meiotic initiation in both males and females. Functional analyses revealed that MEIOSIN acts as a transcription factor together with STRA8, and that both factors are critical for driving meiotic gene activation. Furthermore, temporally restricted expression of MEIOSIN leads to meiotic entry decision during spermatogenesis. The present study demonstrates that MEIOSIN, in collaboration with STRA8, plays a central role in regulating the mitosis to meiosis germ cell fate decision in mammals.
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http://dx.doi.org/10.1016/j.devcel.2020.01.010DOI Listing
February 2020

Mesenchymal-epithelial transition regulates initiation of pluripotency exit before gastrulation.

Development 2020 02 3;147(3). Epub 2020 Feb 3.

International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto 860-0811, Japan

The pluripotent epiblast gives rise to all tissues and organs in the adult body. Its differentiation starts at gastrulation, when the epiblast generates mesoderm and endoderm germ layers through epithelial-mesenchymal transition (EMT). Although gastrulation EMT coincides with loss of epiblast pluripotency, pluripotent cells in development and can adopt either mesenchymal or epithelial morphology. The relationship between epiblast cellular morphology and its pluripotency is not well understood. Here, using chicken epiblast and mammalian pluripotency stem cell (PSC) models, we show that PSCs undergo a mesenchymal-epithelial transition (MET) prior to EMT-associated pluripotency loss. Epiblast MET and its subsequent EMT are two distinct processes. The former, a partial MET, is associated with reversible initiation of pluripotency exit, whereas the latter, a full EMT, is associated with complete and irreversible pluripotency loss. We provide evidence that integrin-mediated cell-matrix interaction is a key player in pluripotency exit regulation. We propose that epiblast partial MET is an evolutionarily conserved process among all amniotic vertebrates and that epiblast pluripotency is restricted to an intermediate cellular state residing between the fully mesenchymal and fully epithelial states.
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http://dx.doi.org/10.1242/dev.184960DOI Listing
February 2020

Mandibular advancement impairs swallowing ability more than head extension but less than mouth opening in the supine position.

Sci Rep 2019 12 27;9(1):20179. Epub 2019 Dec 27.

Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, Suita, Japan.

Mandibular advancement in the supine position may influence swallowing during dental treatment under intravenous sedation. This study investigated the influence of mandibular advancement in the supine position on swallowing ability, compared with head extension and mouth opening. The water swallowing test was performed in 13 healthy, awake, supine, adult subjects under four head and mandibular positions. An electromyogram of the suprahyoid muscles was recorded; the duration and peak amplitude were examined. A greater volume of water remained in the mouth during mouth opening and mandibular advancement relative to the neutral position; the volume in the mandibular advancement position was larger and smaller than that in the head extension position and during mouth opening, respectively. The duration of the electromyogram in the head extension position was longer than that in the mandibular advancement position, without differences in the amplitude. Thus, swallowing ability in the supine position was more impaired with mandibular advancement, relative to neutral and head extension positions, but less than that observed with mouth opening. Although unconfirmed by electromyogram, our findings suggest that head extension might improve airway patency by reducing the impairment of swallowing ability compared with mandibular advancement.
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http://dx.doi.org/10.1038/s41598-019-56843-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934452PMC
December 2019

Bilateral Parkinson's disease model rats exhibit hyperalgesia to subcutaneous formalin administration into the vibrissa pad.

PLoS One 2019 5;14(12):e0225928. Epub 2019 Dec 5.

Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan.

We bilaterally injected 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of rats and developed bilateral Parkinson's disease (PD) model rats in order to experimentally investigate the neural mechanisms underlying the alteration of nociception in the orofacial region of patients with PD. We explored the effects of dopamine depletion on nociception by investigating behavioral responses (face rubbing) triggered by subcutaneous administration of formalin into the vibrissa pad. We also assessed the number of c-Fos-immunoreactive (c-Fos-IR) cells in the superficial layers of the trigeminal spinal subnucleus caudalis (Vc). Subcutaneous formalin administration evoked a two-phase increase in face rubbing. We observed the first increase 0-5 min after formalin administration (first phase) and the second increase 10-60 min after administration (second phase). The number of face rubbing behaviors of 6OHDA-injected rats did not significantly change compared with saline-injected rats in both phases. Significant increase of c-Fos-IR cells in the Vc was found in 6-OHDA-injected rats after formalin administration compared with those in saline-injected rats after formalin administration. We also assessed expression of c-Fos-IR cells in the paraventricular nucleus (PVN), and significant decrease of c-Fos-IR cells in the PVN of 6-OHDA-injected rats was found. Taken together, these findings suggest that bilateral dopaminergic denervation evoked by 6-OHDA administration causes hyperalgesia in the trigeminal region and the PVN may be involved in the hyperalgesia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225928PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894844PMC
March 2020

Age-based prediction of uncuffed tracheal tube size in children to prevent inappropriately large tube selection: a retrospective analysis.

BMC Anesthesiol 2019 08 7;19(1):141. Epub 2019 Aug 7.

Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, 1-8 Yamada-Oka, Suita, Osaka, 565-0871, Japan.

Background: This study aims to validate our previously reported prediction technique for uncuffed tracheal tube (TT) sizes in children younger than 2 years of age based on a calculated outer diameter (OD, mm) in each patient according to the regression equation OD = 0.00223 × age (day) + 4.88 and to investigate a better method to select initial TT sizes to decrease re-intubation frequency, especially since large tubes can damage the trachea.

Methods: We included patients younger than 2 years of age who underwent oral surgery under general anesthesia with tracheal intubation between July 2011 and December 2016 at the Osaka University Dental Hospital. The OD of the actual TT and the age in days were extracted from anesthesia records. Agreement rates, estimated numbers of required tubes, and size reduction frequencies were compared to obtain recommended OD (OD) values in 2 selection groups: "average selection" in the range "nearest to the OD value (OD - 0.35 < OD ≤ OD + 0.35)" and "safe selection" in the range "nearest to the value below OD (OD - 0.7 < OD ≤ OD)".

Results: The agreement rates for an OD in the average selection and safe selection groups were 60.8 and 55.1%, respectively (P = 0.001). The estimated number of required tubes per patient were 1.40 ± 0.51 and 1.47 ± 0.55 (P < 0.001), respectively. The estimated frequencies of size reductions were 13.3 and 4.0% (P < 0.001), respectively.

Conclusions: Because the size reduction frequency is lower despite a slightly higher number of required TTs, selecting an OD based on "safe selection" parameters is desirable to avoid complications due to intubation with larger TTs.
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http://dx.doi.org/10.1186/s12871-019-0818-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686558PMC
August 2019

Klf5 suppresses ERK signaling in mouse pluripotent stem cells.

PLoS One 2018 19;13(11):e0207321. Epub 2018 Nov 19.

Department of Stem Cells and Human Disease Models, Research Center for Animal Life Science, Shiga University of Medical Science, Seta, Tsukinowa-cho, Otsu, Shiga, Japan.

Mouse embryonic stem cells (ESCs) are pluripotent stem cells, which have the ability to differentiate into all three germ layers: mesoderm, endoderm, and ectoderm. Proper levels of phosphorylated extracellular signal-regulated kinase (pERK) are critical for maintaining pluripotency, as elevated pERK evoked by fibroblast growth factor (FGF) receptor activation results in differentiation of ESCs, while, conversely, reduction of pERK by a MEK inhibitor maintains a pluripotent ground state. However, mechanisms underlying proper control of pERK levels in mouse ESCs are not fully understood. Here, we find that Klf5, a Krüppel-like transcription factor family member, is a component of pERK regulation in mouse ESCs. We show that ERK signaling is overactivated in Klf5-KO ESCs and the overactivated ERK in Klf5-KO ESCs is suppressed by the introduction of Klf5, but not Klf2 or Klf4, indicating a unique role for Klf5 in ERK suppression. Moreover, Klf5 regulates Spred1, a negative regulator of the FGF-ERK pathway. Klf5 also facilitates reprogramming of EpiSCs into a naïve state in combination with a glycogen synthase kinase 3 inhibitor and LIF, and in place of a MEK inhibitor. Taken together, these results show for the first time that Klf5 has a unique role suppressing ERK activity in mouse ESCs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207321PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242311PMC
April 2019

Dexmedetomidine and Midazolam Sedation Reduces Unexpected Patient Movement During Dental Surgery Compared With Propofol and Midazolam Sedation.

J Oral Maxillofac Surg 2019 Jan 10;77(1):29-41. Epub 2018 Jul 10.

Professor, Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, Osaka, Japan.

Purpose: Owing to its unpredictability, unexpected patient movement is one of the most important problems during surgery while under monitored anesthesia care with sedation. The purpose of this study was to compare unexpected patient movement during dental surgery while under dexmedetomidine and propofol sedation.

Materials And Methods: The authors designed and implemented a prospective randomized controlled trial. Patients undergoing dental surgery requiring intravenous sedation were randomly assigned to dexmedetomidine and midazolam (dexmedetomidine group) or propofol and midazolam (propofol group) sedation. In each group, midazolam 0.02 mg/kg was administered in conjunction with continuous administration of dexmedetomidine or propofol to maintain a bispectral index value of 70 to 80. Unexpected patient movement interfering with the procedure was defined as acceptable, defined as no body movement or only 1 controllable movement, or unacceptable, defined as at least 2 controllable movements or any uncontrollable movement. The primary outcome was unexpected patient movement, and the secondary outcome was defined as snoring and cough reflex. Other variables included demographic and procedural characteristics. Continuous or ordinal variables were analyzed using the Student t test or Mann-Whitney test. Dichotomous or categorical variables were analyzed using the χ test or Fisher exact test. A P value less than.05 was considered statistically significant.

Results: Eighty-eight patients were enrolled in the study (dexmedetomidine group, n = 44; propofol group, n = 44). There were no relevant differences between groups for demographics and baseline variables. Intraoperative unacceptable patient movement occurred more commonly in the propofol group (n = 13; 30%) than in the dexmedetomidine group (n = 4; 9%; P = .015). Intraoperative snoring occurred more commonly in the dexmedetomidine than in the propofol group (P = .045). Incidence and number of cough reflexes were comparable between groups.

Conclusion: Dexmedetomidine and midazolam sedation decreases unexpected patient movement during dental surgery compared with propofol and midazolam sedation.
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http://dx.doi.org/10.1016/j.joms.2018.07.002DOI Listing
January 2019

Overlapping functions of Krüppel-like factor family members: targeting multiple transcription factors to maintain the naïve pluripotency of mouse embryonic stem cells.

Development 2018 05 30;145(10). Epub 2018 May 30.

Laboratory for Pluripotent Stem Cell Studies, RIKEN Center for Developmental Biology (CDB), 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan

Krüppel-like factors (Klfs) have a pivotal role in maintaining self-renewal of mouse embryonic stem cells (mESCs). The functions of three Klf family members (Klf2, Klf4 and Klf5) have been identified, and are suggested to largely overlap. For further dissection of their functions, we applied an inducible knockout system for these Klf family members and assessed the effects of combinatorial loss of function. As a result, we confirmed that any one of Klf2, Klf4 and Klf5 was sufficient to support self-renewal, whereas the removal of all three compromised it. The activity of any single transcription factor, except for a Klf family member, was not sufficient to restore self-renewal of triple-knockout mESCs. However, some particular combinations of transcription factors were capable of the restoration. The triple-knockout mESCs were successfully captured at primed state. These data indicate that the pivotal function of a Klf family member is transduced into the activation of multiple transcription factors in a naïve-state-specific manner.
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http://dx.doi.org/10.1242/dev.162404DOI Listing
May 2018

The principles that govern transcription factor network functions in stem cells.

Authors:
Hitoshi Niwa

Development 2018 03 14;145(6). Epub 2018 Mar 14.

Department of Pluripotent Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan

Tissue-specific transcription factors primarily act to define the phenotype of the cell. The power of a single transcription factor to alter cell fate is often minimal, as seen in gain-of-function analyses, but when multiple transcription factors cooperate synergistically it potentiates their ability to induce changes in cell fate. By contrast, transcription factor function is often dispensable in the maintenance of cell phenotype, as is evident in loss-of-function assays. Why does this phenomenon, commonly known as redundancy, occur? Here, I discuss the role that transcription factor networks play in collaboratively regulating stem cell fate and differentiation by providing multiple explanations for their functional redundancy.
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http://dx.doi.org/10.1242/dev.157420DOI Listing
March 2018

Co-precipitation molecules hemopexin and transferrin may be key molecules for fibrillogenesis in TTR V30M amyloidogenesis.

Transgenic Res 2018 02 29;27(1):15-23. Epub 2017 Dec 29.

Division of Medical Informatics and Bioinformatics, Kobe University Hospital, Kobe, 650-0017, Japan.

The disease model of familial amyloidotic polyneuropathy-7.2-hMet30 mice-manifests amyloid deposition that consists of a human amyloidogenic mutant transthyretin (TTR) (TTR V30M). Our previous study found amyloid deposits in 14 of 27 7.2-hMet30 mice at 21-24 months of age. In addition, non-fibrillar TTR deposits were found in amyloid-negative 7.2hMet30 mice. These results suggested that TTR amyloidogenesis required not only mutant TTR but also an additional factor (or factors) as an etiologic molecule. To determine the differences in serum proteome in amyloid-positive and amyloid-negative mice in the 7.2-hMet30 model, we used proteomic analyses and studied serum samples obtained from these mice. Hemopexin (HPX) and transferrin (Tf) were detected in the serum samples from amyloid-positive mice and were also found in amyloid deposits via immunohistochemistry, but serum samples from amyloid-negative mice did not contain HPX and Tf. These two proteins were also not detected in non-fibrillar TTR deposits. In addition, in silico analyses suggested that HPX and Tf facilitate destabilization of TTR secondary structures and misfolding of TTR. These results suggest that HPX and Tf may be associated with TTR amyloidogenesis after fibrillogenesis in vivo.
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http://dx.doi.org/10.1007/s11248-017-0054-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847157PMC
February 2018

Anaphylaxis with delayed appearance of skin manifestations during general anesthesia: two case reports.

BMC Res Notes 2017 Jul 24;10(1):308. Epub 2017 Jul 24.

Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, 1-8, Yamadaoka, Suita, Osaka, 565-0871, Japan.

Background: Anaphylaxis is difficult to diagnose in the absence of skin or mucosal signs and symptoms. We report two cases of anaphylaxis under general anesthesia, in which the initial presentation was in the form of respiratory signs, followed by skin manifestations 10-15 min later. Diagnosis of anaphylaxis was delayed because skin symptoms were absent early on in the presentation.

Case Presentation: In the first case, a 23-year-old male patient with jaw deformity was scheduled to undergo maxillary alveolar osteotomy. After intubation, auscultation indicated a sudden decrease in breath sounds, together with severe hypotension. Approximately 10 min later, flushing of the skin and urticaria on the thigh appeared and spread widely throughout the body. In the second case, a 21-year-old female patient with jaw deformity was scheduled to undergo maxillomandibular osteotomy. Twenty minutes after the start of dextran infusion, her lungs suddenly became difficult to ventilate, and oxygen saturation decreased to 90%. Approximately 15 min later, flushing of the skin and urticaria were observed.

Conclusion: In both cases, there was a time lag between the appearance of respiratory and skin symptoms, which resulted in a delay in the diagnosis, and hence, treatment of anaphylaxis. Our experience highlights the fact that it is difficult to diagnose anaphylaxis under general anesthesia.
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http://dx.doi.org/10.1186/s13104-017-2624-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525218PMC
July 2017

Airway management for glossopexy in infants with micrognathia and obstructive breathing.

J Clin Anesth 2017 Feb 1;36:127-132. Epub 2016 Dec 1.

Department of Dental Anesthesiology, Graduate School of Dentistry, Osaka University, 1-8, Yamadaoka, Suita, Osaka 565-0871, Japan.

Study Objectives: To identify airway management and tracheal intubation techniques for glossopexy in infants with preexisting airway obstruction under general anesthesia.

Design: Retrospective, observational study.

Settings: Operating room of a university hospital between January 2003 and March 2015. All operations were performed by oral and maxillofacial surgeons.

Patients: Thirteen patients who received general anesthesia for glossopexy and reversal after 7 months.

Measurements: The medical records of these infants were retrospectively examined to evaluate the following: age, sex, height and weight at surgery, preoperative airway status, tracheal intubation route (oral or nasal), method for inducing general anesthesia, method for establishing the airway during mask ventilation, apparatus used for tracheal intubation, Cormack-Lehane classification when using a Macintosh laryngoscope and video laryngoscope, and the need for airway placement after extubation.

Results: Prone positioning and/or an airway of some kind before surgery were required in 38.5% of infants needing glossopexy. Difficult mask ventilation was common, occurring in 50% of the patients, and the incidence of airway placement during mask ventilation was significantly higher in infants with preoperative complete or incomplete obstruction (100%) than in infants with snoring (25%). Of these high-risk infants, 25% could not be intubated with a direct laryngoscope or Glidescope Cobalt and required fiberoptic intubation.

Conclusion: There are severe cases of infants with difficult mask ventilation and difficult tracheal intubation in which a fiberscope is required because video laryngoscopy fails to improve the view of the larynx.
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http://dx.doi.org/10.1016/j.jclinane.2016.10.019DOI Listing
February 2017

c-Fos expression in the parabrachial nucleus following intraoral bitter stimulation in the rat with dietary-induced zinc deficiency.

Brain Res 2017 03 19;1659:1-7. Epub 2017 Jan 19.

Department of Oral Anatomy and Developmental Biology, Osaka University Graduate School of Dentistry, Japan.

Zinc deficiency causes various symptoms including taste disorders. In the present study, changes in expression of c-Fos immunoreactivity in neurons of the parabrachial nucleus (PBN), one of the relay nuclei for transmission of gustatory information, after bitter stimulation to the dorsal surface of the tongue were examined in zinc-deficient rats. Experimental zinc-deficient animals were created by feeding a low-zinc diet for 4weeks, and showed the following symptoms of zinc deficiency: low body weight, low serum zinc content and behavioral changes to avoid bitter stimulation. In normal control animals, intraoral application of 1mM quinine caused increased numbers of c-Fos-immunoreactive (c-Fos-IR) neurons in the external lateral subnucleus and external medial subnucleus of the PBN (elPBN and emPBN, respectively) compared with application of distilled water. However, in the zinc-deficient animals, the numbers of c-Fos-IR neurons in the elPBN and emPBN did not differ significantly between application of quinine and distilled water. After feeding the zinc-deficient animals a normal diet for 4weeks, the symptoms of zinc deficiency recovered, and the expression of c-Fos-IR neurons following intraoral bitter stimulation became identical to that in the normal control animals. The present results indicate that dietary zinc deficiency causes alterations to neuronal activities in the gustatory neural circuit, and that these neuronal alterations can be reversed by changing to a normal diet.
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http://dx.doi.org/10.1016/j.brainres.2017.01.020DOI Listing
March 2017

Trigeminal nervous system sensitization by infraorbital nerve injury enhances responses in a migraine model.

Cephalalgia 2017 Dec 12;37(14):1317-1328. Epub 2016 Nov 12.

Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan.

Background Although the peripheral and central sensitizations of trigeminal nervous system may be one of the important factors of migraine, the precise mechanism is not fully understood. In this study, we examined the influence of the sensitization of the second division of the trigeminal nerve (V2) by chronic constriction injury (CCI) of the infraorbital nerve (ION) on migraine headache, using the capsaicin-induced migraine model. Methods Male Sprague-Dawley rats were assigned to four groups: (a) sham surgery and topical-dural vehicle application (Sham + Vehicle) group, (b) CCI-ION and topical-dural vehicle application (CCI-ION + Vehicle) group, (c) sham surgery and topical-dural capsaicin application (Sham + Capsaicin) group, (d) CCI-ION and topical-dural capsaicin application (CCI-ION + Capsaicin) group. Behavioral testing and immunohistochemical staining were performed. Results In the behavioral test, the Sham + Capsaicin group showed significantly longer duration of immobilization and shorter duration of exploration compared with the Sham + Vehicle group, which is similar to clinical features of migraine patients. Moreover, CCI-ION enhanced these effects in the CCI-ION + Capsaicin group. Immunohistochemical staining for phospho-extracellular signal-related kinase (pERK) in the trigeminal ganglion (TG) containing first and second divisions of the trigeminal nerve and the trigeminocervical complex (TCC) revealed that pERK expression was significantly increased in the CCI-ION + Capsaicin group compared with the other groups. However, comparing between effects of the peripheral and central sensitizations (in the TG and TCC), from our results, peripheral sensitization would play a much less or not significant role. Conclusions These data demonstrate that the sensitization of V2 could influence the activation and the sensitization of the first division of the trigeminal nerve in the TCC, subsequently exacerbating pain sensation and pain-related behaviors. We have shown for the first time that the existence of the central sensitization of V2 can be an exacerbating factor for migraine related nociceptive thresholds/activation.
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http://dx.doi.org/10.1177/0333102416678387DOI Listing
December 2017
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