Updated on 2024/04/24

写真a

 
NOZAKI, Chihiro
 
Affiliation
Faculty of Science and Engineering, Global Center for Science and Engineering
Job title
Associate Professor(without tenure)
Degree
博士 ( 星薬科大学 )
Mail Address
メールアドレス
Profile

My research interest was always based on neuroinflammation and neuronal hypersensitivity under the pathological state.

Currently I'm working on the DFG-funded project "Role of endocannabinoid system on the modulation of migraine", to evaluate if FAAH-CB1 signaling contributes to the modulation of migraine and/or medication overuse headache pain including its gender difference.

Also I'm interested in if endocannabinoid systems will modulate any kind of diseases which induces pain/neuroinflammation such as diabetes, obesity, allergy or Alzheimer's disease, as CB1 signalings involves to the metabolisms while CB2 signalings contributes to the immune systems.

Research Experience

  • 2020.04
    -
    Now

    Waseda University   Faculty of Science and Engineering   Associate professor

  • 2019.12
    -
    2020.03

    東京理科大学生命医科学研究所   炎症・免疫難病制御部門   プロジェクト研究員

  • 2016.01
    -
    2019.11

    University of Bonn   Institute of Molecular Psychiatry   DFG Eigene Stelle(Temporary PI)

  • 2011.10
    -
    2015.12

    Uniersity of Bonn   Institute of Molecular Psychiatry   Postdoctoral Fellow

  • 2007.07
    -
    2011.09

    Institut de génétique et de biologie moléculaire et cellulaire (IGBMC)   Medecine translationnelle & Neurogenetique   Postdoctoral researcher

  • 2006.04
    -
    2006.10

    Aalborg University   Center for Sensory-Motor Interaction   Research Assistant

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Education Background

  • 2004.04
    -
    2007.03

    Hoshi University   Graduate School of Pharmaceutical Sciences   Department of Pathophysiology & Therapeutics  

  • 2002.04
    -
    2004.03

    Kyoto Institute of Technology   Graduate School of Science and Technology   Division of Polymer Science and Engineering  

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    Kyoto Institute of Technology   Faculty of Textile Science   Department of Polymer Science and Engineering  

Professional Memberships

  •  
     
     

    International Cannabinoid Research Society

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    Society for Neuroscience

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    German Neuroscience Society

  •  
     
     

    THE JAPANESE PHARMACOLOGICAL SOCIETY

  •  
     
     

    International Narcotic Research Conference

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    International Association for the Study of Pain

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Research Areas

  • Pharmacology / Neuroscience-general

Research Interests

  • Diabetes

  • Inflammation

  • Leptin

  • Obesity

  • Metabolic syndrome

  • Neuroinflammation

  • Headache

  • Drug

  • Pharmacology

  • Migraine

  • Cannabinoid

  • Opioid

  • Pain

▼display all

Awards

  • Excelent Young Researcher candidate 2018

    2018   Japan Society for the Promotion of Science  

    Winner: Chihiro Nozaki

  • Financement de projets impliquant des post-doctorant en France

    2009.01   Fondation pour la Recherche Medicale  

    Winner: Chihiro Nozaki

  • Travel Award

    2005.08   International Narcotic Research Conference (INRC)  

    Winner: Chihiro Nozaki

 

Papers

  • Age-dependent Alteration in Mitochondrial Dynamics and Autophagy in Hippocampal Neuron of Cannabinoid CB1 Receptor-deficient Mice.

    Kosuke Kataoka, Andras Bilkei-Gorzo, Chihiro Nozaki, Akinobu Togo, Keiichiro Nakamura, Keisuke Ohta, Andreas Zimmer, Toru Asahi

    Brain research bulletin   160   40 - 49  2020.07  [Refereed]  [International journal]

     View Summary

    Endocannabinoid system activity contributes to the homeostatic defense against aging and thus may counteract the progression of brain aging. The cannabinoid type 1 (CB1) receptor activity declines with aging in the brain, which impairs neuronal network integrity and cognitive functions. However, the underlying mechanisms that link CB1 activity and memory decline remain unknown. Mitochondrial activity profoundly influences neuronal function, and age-dependent mitochondrial activity change is one of the known hallmarks of brain aging. As CB1 receptor is expressed on mitochondria and may regulate neuronal energy metabolism in hippocampus, we hypothesized that CB1 receptors might influence mitochondria in hippocampal neurons. Here, we found that CB1 receptor significantly affected mitochondrial autophagy (mitophagy) and morphology in an age-dependent manner. Serine 65-phosphorylated ubiquitin, a key marker for mitophagy, was reduced in adult CB1-deficient mice (CB1-KO) compared to those in wild type controls, particularly in CA1 pyramidal cell layer. Transmission electron microscopy (TEM) analysis showed reduced mitophagy-like events in hippocampus of adult CB1-KO. TEM analysis also showed that mitochondrial morphology in adult CB1-KO mice was altered shown by an increase in thin and elongated mitochondria in hippocampal neurons. 3D reconstruction of mitochondrial morphology after scanning electron microscopy additionally revealed an enhanced density of interconnected mitochondria. Altogether, these findings suggest that reduced CB1 signaling in CB1-KO mice leads to reduced mitophagy and abnormal mitochondrial morphology in hippocampal neurons during aging. These mitochondrial changes might be due to the impairments in mitochondrial quality control system, which links age-related decline in CB1 activity and impaired memory.

    DOI PubMed

    Scopus

    18
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  • CB2 receptor deletion on myeloid cells enhanced mechanical allodynia in a mouse model of neuropathic pain.

    Elisa Nent, Chihiro Nozaki, Anne-Caroline Schmöle, David Otte, Andreas Zimmer

    Scientific reports   9 ( 1 ) 7468 - 7468  2019.05  [Refereed]  [International journal]

     View Summary

    Neuropathic pain can develop after nerve injury, leading to a chronic condition with spontaneous pain and hyperalgesia. Pain is typically restricted to the side of the injured nerve, but may occasionally spread to the contralateral side, a condition that is often referred to as mirror-image pain. Mechanisms leading to mirror-image pain are not completely understood, but cannabinoid CB2 receptors have been implicated. In this study, we use genetic mouse models to address the question if CB2 receptors on neurons or on microglia/macrophages are involved. First, we show that a GFP reporter protein under control of the CB2 promoter is induced upon partial sciatic nerve ligation in spinal cord, dorsal root ganglia, and highest in sciatic nerve macrophages, but not in neurons. Mice which lack CB2 receptors specifically on myeloid cells (microglia, macrophages) developed a mirror-image allodynia [treatment F1,48 = 45.69, p < 0.0001] similar to constitutive CB2 receptor knockout mice [treatment F1,70 = 92.41, p < 0.0001]. Such a phenotype was not observed after the deletion of CB2 from neurons [treatment F1,70 = 0.1315, p = 0.7180]. This behavioral pain phenotype was accompanied by an increased staining of microglia in the dorsal horn of the spinal cord, as evidenced by an enhanced Iba 1 expression [CB2KO, p = 0.0175; CB2-LysM, p = 0.0425]. Similarly, myeloid-selective knockouts showed an increased expression of the leptin receptor in the injured ipsilateral sciatic nerve, thus further supporting the notion that leptin signaling contributes to the increased neuropathic pain responses of CB2 receptor knockout mice. We conclude that CB2 receptors on microglia and macrophages, but not on neurons, modulate neuropathic pain responses.

    DOI PubMed

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    23
    Citation
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  • Involvement of leptin signaling in the development of cannabinoid CB2 receptor-dependent mirror image pain.

    Chihiro Nozaki, Elisa Nent, Andras Bilkei-Gorzo, Andreas Zimmer

    Scientific reports   8 ( 1 ) 10827 - 10827  2018.07  [Refereed]  [International journal]

    Authorship:Lead author

     View Summary

    Neuropathic pain typically appears in a region innervated by an injured or diseased nerve and, in some instances, also on the contralateral side. This so-called mirror image pain is often observed in mice lacking CB2 receptors after sciatic nerve injury, but the underlying mechanisms for this phenotype largely remain unclear. Here we focused on peripheral leptin signaling, which modulates neuropathic pain development and interacts with the endocannabinoid system. Leptin production is induced at the site of nerve injury in CB2-deficient mice (CB2-KO) mice and wild type controls (WT). However, induction of leptin receptor expression was only observed in the injured nerve of CB2-KO mice. This was paralleled by a stimulation of the leptin receptor-downstream STAT3 signaling and an infiltration of F4/80-positive macrophages. Interestingly, an upregulation of leptin receptor expression STAT3 activity and macrophage infiltration was also observed on the non-injured nerve of CB2-KO mice thus reflecting the mirror image pain in CB2-KO animals. Importantly, perineurally-administered leptin-neutralizing antibodies reduced mechanical hyperalgesia, blocked mirror image pain and inhibited the recruitment of F4/80-positive macrophages. These results identify peripheral leptin signaling as an important modulator of CB2 signaling in neuropathic pain.

    DOI PubMed

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    8
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  • Inhibition of FAAH reduces nitroglycerin-induced migraine-like pain and trigeminal neuronal hyperactivity in mice.

    Chihiro Nozaki, Astrid Markert, Andreas Zimmer

    European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology   25 ( 8 ) 1388 - 96  2015.08  [Refereed]  [International journal]

    Authorship:Lead author, Corresponding author

     View Summary

    There is evidence to suggest that a dysregulation of endocannabinoid signaling may contribute to the etiology and pathophysiology of migraine. Thus, patients suffering from chronic migraine or medication overuse headache showed alterations in the activity of the arachidonoylethanolamide (AEA) degrading enzyme fatty acid amide hydrolase (FAAH) and a specific AEA membrane transporter, alongside with changes in AEA levels. The precise role of different endocannabinoid system components is, however, not clear. We have therefore investigated mice with a genetic deletion of the two main cannabinoid receptors CB1 and CB2, or the main endocannabinoid degrading enzymes, FAAH and monoacylglycerol lipase (MAGL), which degrades 2-arachidonoylglycerol (2-AG), in a nitroglycerine-induced animal model of migraine. We found that nitroglycerin-induced mechanical allodynia and neuronal activation of the trigeminal nucleus were completely abolished in FAAH-deficient mice. To validate these results, we used two structurally different FAAH inhibitors, URB597 and PF3945. Both inhibitors also dose-dependently blocked nitroglycerin-induced hyperalgesia and the activation of trigeminal neurons. The effects of the genetic deletion of pharmacological blockade of FAAH are mediated by CB1 receptors, because they were completely disrupted with the CB1 antagonist rimonabant. These results identify FAAH as a target for migraine pharmacotherapy.

    DOI PubMed

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    31
    Citation
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  • In vivo properties of KNT-127, a novel delta opioid receptor agonist: receptor internalization, antihyperalgesia and antidepressant effects in mice

    C. Nozaki, H. Nagase, T. Nemoto, A. Matifas, B. L. Kieffer, C. Gaveriaux-Ruff

    BRITISH JOURNAL OF PHARMACOLOGY   171 ( 23 ) 5376 - 5386  2014.12  [Refereed]

    Authorship:Lead author, Corresponding author

     View Summary

    Background and PurposeActivation of opioid (DOP) receptors regulates pain and emotional responses, and also displays ligand-biased agonism. KNT-127 (1,2,3,4,4a,5,12,12a-octahydro-2-methyl-4a,1-([1,2]benzenomethano)-2,6-diazanaphthacene-12a,17-diol) is a novel DOP receptor agonist inducing analgesia and antidepressant effects in mice. Here, we have assessed KNT-127 for (i) analgesia against chronic inflammatory pain; (ii) effects on depression, locomotion and DOP receptor internalization; and (iii) for cross-tolerance to analgesic and antidepressant effects of acute treatment by other DOP receptor agonists.
    Experimental ApproachInflammatory pain was induced by complete Freund's adjuvant injection into tail or hindpaw, and thermal and mechanical sensitivities were determined in mice. Locomotor and antidepressant-like effects were measured using actimetry and forced swim test respectively. In vivoKNT-127 selectivity and internalization were assessed using DOP receptor knockout mice and knock-in mice expressing fluorescent-tagged DOP receptors. KNT-127 was injected acutely at 0.1-10.0mg&lt;bold&gt;kg(&lt;/bold&gt;-1) or administered chronically at 5mg&lt;bold&gt;kg(&lt;/bold&gt;-1) daily over 5 days.
    Key ResultsAcute treatment with KNT-127 reversed inflammatory hyperalgesia, produced an antidepressant-like effect but induced neither hyperlocomotion nor receptor sequestration. Chronic treatment with KNT-127 induced tolerance and cross-tolerance to SNC80-induced analgesia, but no tolerance to SNC80-evoked hyperlocomotor or antidepressant-like effects.
    Conclusions and ImplicationsThe DOP receptor agonist KNT-127 induced agonist-specific acute and chronic responses, at both behavioural and cellular levels. It displays activities similar to the other recently reported DOP agonists, AR-M1000390, ADL5747 and ADL5859, and differs from SNC80. SNC80 differs from the other DOP receptor agonists including KNT-127, by exhibiting ligand-biased tolerance at this receptor.

    DOI PubMed

    Scopus

    36
    Citation
    (Scopus)
  • δ-Opioid mechanisms for ADL5747 and ADL5859 effects in mice: analgesia, locomotion, and receptor internalization.

    Chihiro Nozaki, Bertrand Le Bourdonnec, David Reiss, Rolf T Windh, Patrick J Little, Roland E Dolle, Brigitte L Kieffer, Claire Gavériaux-Ruff

    The Journal of pharmacology and experimental therapeutics   342 ( 3 ) 799 - 807  2012.09  [Refereed]  [International journal]

    Authorship:Lead author

     View Summary

    N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4'-piperidine]-4-yl) benzamide (ADL5859) and N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4'-piperidine]-4-yl)benzamide (ADL5747) are novel δ-opioid agonists that show good oral bioavailability and analgesic and antidepressive effects in the rat and represent potential drugs for chronic pain treatment. Here, we used genetic approaches to investigate molecular mechanisms underlying their analgesic effects in the mouse. We tested analgesic effects of ADL5859 and ADL5747 in mice by using mechanical sensitivity measures in both complete Freund's adjuvant and sciatic nerve ligation pain models. We examined their analgesic effects in δ-opioid receptor constitutive knockout (KO) mice and mice with a conditional deletion of δ-receptor in peripheral voltage-gated sodium channel (Nav)1.8-expressing neurons (cKO mice). Both ADL5859 and ADL5747, and the prototypical δ agonist 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethyl-piperazin-1-yl]-(3-methoxyphenyl)methyl]-N,N-diethyl-benzamide (SNC80) as a control, significantly reduced inflammatory and neuropathic pain. The antiallodynic effects of all three δ-opioid agonists were abolished in constitutive δ-receptor KO mice and strongly diminished in δ-receptor cKO mice. We also measured two other well described effects of δ agonists, increase in locomotor activity and agonist-induced receptor internalization by using knock-in mice expressing enhanced green fluorescence protein-tagged δ receptors. In contrast to SNC80, ADL5859 and ADL5747 did not induce either hyperlocomotion or receptor internalization in vivo. In conclusion, both ADL5859 and ADL5747 showed efficient pain-reducing properties in the two models of chronic pain. Their effects were mediated by δ-opioid receptors, with a main contribution of receptors expressed on peripheral Nav1.8-positive neurons. The lack of in vivo receptor internalization and locomotor activation, typically induced by SNC80, suggests agonist-biased activity at the receptor for the two drugs.

    DOI PubMed J-GLOBAL

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    68
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  • The delta opioid receptor: an evolving target for the treatment of brain disorders.

    Amynah A Pradhan, Katia Befort, Chihiro Nozaki, Claire Gavériaux-Ruff, Brigitte L Kieffer

    Trends in pharmacological sciences   32 ( 10 ) 581 - 90  2011.10  [Refereed]  [Invited]  [International journal]

     View Summary

    Compared to the better-known mu opioid receptor, delta opioid receptors have been relatively understudied. However, the development of highly selective delta opioid agonists and the availability of genetic mouse models have extended our knowledge of delta opioid receptors in vivo. Here we review recent developments in the characterization of delta opioid receptor biology and aspects of delta opioid receptor function that have potential for therapeutic targeting. Preclinical data have confirmed that delta opioid receptor activation reduces persistent pain and improves negative emotional states; clinical trials have been initiated to assess the effectiveness of delta opioid agonists in chronic pain and depression. Furthermore, a possible role for these receptors in neuroprotection is being investigated. The usefulness of targeting delta opioid receptors in drug abuse remains open and a role for these receptors in impulse control disorders is emerging. Finally, the recent demonstration of biased agonism at the delta opioid receptor in vivo opens novel perspectives towards targeting specific therapeutic effects through drug design.

    DOI PubMed J-GLOBAL

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    240
    Citation
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  • Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit.

    Chihiro Nozaki, Angela Maria Vergnano, Dominique Filliol, Abdel-Mouttalib Ouagazzal, Anne Le Goff, Stéphanie Carvalho, David Reiss, Claire Gaveriaux-Ruff, Jacques Neyton, Pierre Paoletti, Brigitte L Kieffer

    Nature neuroscience   14 ( 8 ) 1017 - 22  2011.07  [Refereed]  [International journal]

    Authorship:Lead author

     View Summary

    Zinc is abundant in the central nervous system and regulates pain, but the underlying mechanisms are unknown. In vitro studies have shown that extracellular zinc modulates a plethora of signaling membrane proteins, including NMDA receptors containing the NR2A subunit, which display exquisite zinc sensitivity. We created NR2A-H128S knock-in mice to investigate whether Zn2+-NR2A interaction influences pain control. In these mice, high-affinity (nanomolar) zinc inhibition of NMDA currents was lost in the hippocampus and spinal cord. Knock-in mice showed hypersensitivity to radiant heat and capsaicin, and developed enhanced allodynia in inflammatory and neuropathic pain models. Furthermore, zinc-induced analgesia was completely abolished under both acute and chronic pain conditions. Our data establish that zinc is an endogenous modulator of excitatory neurotransmission in vivo and identify a new mechanism in pain processing that relies on NR2A NMDA receptors. The study also potentially provides a molecular basis for the pain-relieving effects of dietary zinc supplementation.

    DOI PubMed J-GLOBAL

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    101
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  • Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia.

    Claire Gaveriaux-Ruff, Chihiro Nozaki, Xavier Nadal, Xavier C Hever, Raphael Weibel, Audrey Matifas, David Reiss, Dominique Filliol, Mohammed A Nassar, John N Wood, Rafael Maldonado, Brigitte L Kieffer

    Pain   152 ( 6 ) 1238 - 1248  2011.06  [Refereed]  [International journal]

     View Summary

    Opioid receptors are major actors in pain control and are broadly distributed throughout the nervous system. A major challenge in pain research is the identification of key opioid receptor populations within nociceptive pathways, which control physiological and pathological pain. In particular, the respective contribution of peripheral vs. central receptors remains unclear, and it has not been addressed by genetic approaches. To investigate the contribution of peripheral delta opioid receptors in pain control, we created conditional knockout mice where delta receptors are deleted specifically in peripheral Na(V)1.8-positive primary nociceptive neurons. Mutant mice showed normal pain responses to acute heat and to mechanical and formalin stimuli. In contrast, mutant animals showed a remarkable increase of mechanical allodynia under both inflammatory pain induced by complete Freund adjuvant and neuropathic pain induced by partial sciatic nerve ligation. In these 2 models, heat hyperalgesia was virtually unchanged. SNC80, a delta agonist administered either systemically (complete Freund adjuvant and sciatic nerve ligation) or into a paw (sciatic nerve ligation), reduced thermal hyperalgesia and mechanical allodynia in control mice. However, these analgesic effects were absent in conditional mutant mice. In conclusion, this study reveals the existence of delta opioid receptor-mediated mechanisms, which operate at the level of Na(V)1.8-positive nociceptive neurons. Delta receptors in these neurons tonically inhibit mechanical hypersensitivity in both inflammatory and neuropathic pain, and they are essential to mediate delta opioid analgesia under conditions of persistent pain. This delta receptor population represents a feasible therapeutic target to alleviate chronic pain while avoiding adverse central effects. The conditional knockout of delta-opioid receptor in primary afferent Na(V)1.8 neurons augmented mechanical allodynia in persistent pain models and abolished delta opioid analgesia in these models.

    DOI PubMed J-GLOBAL

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    135
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  • Ligand-directed trafficking of the δ-opioid receptor in vivo: two paths toward analgesic tolerance.

    Amynah A A Pradhan, Wendy Walwyn, Chihiro Nozaki, Dominique Filliol, Eric Erbs, Audrey Matifas, Christopher Evans, Brigitte L Kieffer

    The Journal of neuroscience : the official journal of the Society for Neuroscience   30 ( 49 ) 16459 - 68  2010.12  [Refereed]  [International journal]

     View Summary

    δ-Opioid receptors are G-protein-coupled receptors that regulate nociceptive and emotional responses. It has been well established that distinct agonists acting at the same G-protein-coupled receptor can engage different signaling or regulatory responses. This concept, known as biased agonism, has important biological and therapeutic implications. Ligand-biased responses are well described in cellular models, however, demonstrating the physiological relevance of biased agonism in vivo remains a major challenge. The aim of this study was to investigate the long-term consequences of ligand-biased trafficking of the δ-opioid receptor, at both the cellular and behavioral level. We used δ agonists with similar binding and analgesic properties, but high [SNC80 ((+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide)]- or low [ARM390 (N,N-diethyl-4-(phenyl-piperidin-4-ylidenemethyl)-benzamide)]-internalization potencies. As we found previously, a single SNC80-but not ARM390-administration triggered acute desensitization of the analgesic response in mice. However, daily injections of either compound over 5 d produced full analgesic tolerance. SNC80-tolerant animals showed widespread receptor downregulation, and tolerance to analgesic, locomotor and anxiolytic effects of the agonist. Hence, internalization-dependent tolerance developed, as a result of generalized receptor degradation. In contrast, ARM390-tolerant mice showed intact receptor expression, but δ-opioid receptor coupling to Ca²+ channels was abolished in dorsal root ganglia. Concomitantly, tolerance developed for agonist-induced analgesia, but not locomotor or anxiolytic responses. Therefore, internalization-independent tolerance was produced by anatomically restricted adaptations leading to pain-specific tolerance. Hence, ligand-directed receptor trafficking of the δ-opioid receptor engages distinct adaptive responses, and this study reveals a novel aspect of biased agonism in vivo.

    DOI PubMed J-GLOBAL

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    117
    Citation
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  • Role of cyclin-dependent kinase 5 in capsaicin-induced cough.

    Junzo Kamei, Shun-suke Hayashi, Yoshiki Takahashi, Chihiro Nozaki

    European journal of pharmacology   566 ( 1-3 ) 181 - 4  2007.07  [Refereed]  [International journal]

     View Summary

    The role of cyclin-dependent kinase 5 (Cdk5) in the capsaicin-induced cough reflex was examined in mice. Pretreatment with inhaled roscovitine, a selective Cdk5 inhibitor, at concentrations of 0.3 to 3 mM inhibited the number of capsaicin-induced coughs in a concentration-dependent manner. Pretreatment with inhaled roscovitine, at a concentration of 3 mM also slightly but significantly inhibited the number of citric acid-induced coughs. The number of capsaicin-induced coughs was significantly reduced when C-fibers were desensitized by the pretreatment with capsaicin. The number of citric acid-induced coughs was slightly but significantly reduced in capsaicin-pretreated mice as compared with that in naive mice. Although the inhalation of roscovitine at a concentration of 3 mM significantly reduced the number of citric acid-induced coughs in naive mice to the level observed in capsaicin-pretreated mice, roscovitine had no effect on the number of citric acid-induced coughs in capsaicin-pretreated mice. These results suggest that Cdk5-dependent factors are involved in C-fiber-mediated cough signaling.

    DOI PubMed J-GLOBAL

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    5
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  • Involvement of mu1-opioid receptor on oxycodone-induced antinociception in diabetic mice.

    Chihiro Nozaki, Junzo Kamei

    European journal of pharmacology   560 ( 2-3 ) 160 - 2  2007.04  [Refereed]  [International journal]

    Authorship:Lead author

     View Summary

    The effect of naloxonazine, a selective mu(1)-opioid receptor antagonist, on oxycodone-induced antinociception was examined in streptozotocin-induced diabetic mice. Oxycodone (5 mg/kg, s.c.) induced significant antinociception in both non-diabetic and diabetic mice. This antinociceptive effect of oxycodone was completely antagonized by pretreatment with naloxonazine (35 mg/kg, s.c.) in both non-diabetic and diabetic mice. The selective kappa-opioid receptor antagonist nor-binaltorphimine (20 mg/kg, s.c.) also antagonized oxycodone-induced antinociception in diabetic mice, but only had a partial effect in non-diabetic mice. These results suggest that although primarily interacts with mu(1)-opioid receptor, kappa-opioid receptors are also strongly involved in oxycodone-induced antinociception.

    DOI PubMed J-GLOBAL

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    21
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  • Possible involvement of opioidergic systems in the antinociceptive effect of the selective serotonin reuptake inhibitors in sciatic nerve-injured mice.

    Chihiro Nozaki, Junzo Kamei

    European journal of pharmacology   552 ( 1-3 ) 99 - 104  2006.12  [Refereed]  [International journal]

    Authorship:Lead author

     View Summary

    The involvement of opioid receptor activation in the antinociceptive effect of either fluvoxamine, a selective serotonin reuptake inhibitor, or serotonin (5-HT) on thermal hyperalgesia and mechanical allodynia in a model of neuropathic pain in mice induced by sciatic nerve ligation was examined. The experiments were conducted 2 or 6 weeks after unilateral sciatic nerve ligation. Ipsilateral thermal hyperalgesia and mechanical allodynia were observed both 2 and 6 weeks after sciatic nerve ligation. Neither s.c. fluvoxamine nor i.t. 5-HT affected sciatic nerve ligation-induced thermal hyperalgesia or mechanical allodynia in mice 2 weeks after sciatic nerve ligation. However, the same dose of either fluvoxamine or 5-HT significantly reduced mechanical allodynia but not thermal hyperalgesia in sciatic nerve ligated mice 6 weeks after surgery. The antinociceptive effect of fluvoxamine on sciatic nerve ligation-induced mechanical allodynia in mice 6 weeks after surgery was completely abolished by pretreatment with either naloxone, a nonselective opioid receptor antagonist, or beta-funaltrexamine, a selective mu-opioid receptor antagonist. Furthermore, pretreatment with naltrindole, a selective delta-opioid receptor antagonist, partially but significantly inhibited the antinociceptive effect of fluvoxamine in sciatic nerve ligated mice at the 6th postoperative week. The antinociceptive effect induced by i.t. 5-HT was also completely antagonized by either naloxone or beta-funaltrexamine, and partially inhibited by naltrindole. However, pretreatment with nor-binaltorphimine, a selective kappa-opioid receptor antagonist, had no effect against either s.c. fluvoxamine- or i.t. 5-HT-induced antinociception. These results suggest that the antinociceptive effect of s.c. fluvoxamine or i.t. 5-HT in the chronic state of sciatic nerve ligation-induced neuropathic pain may be related to opioidergic activity, mainly through the activation of spinal mu- and delta-opioid receptors.

    DOI PubMed J-GLOBAL

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    17
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  • Changes in emotional behavior of mice in the hole-board test after olfactory bulbectomy.

    Akiyoshi Saitoh, Noritaka Hirose, Mitsuhiko Yamada, Misa Yamada, Chihiro Nozaki, Takuma Oka, Junzo Kamei

    Journal of pharmacological sciences   102 ( 4 ) 377 - 86  2006.12  [Refereed]  [Domestic journal]

     View Summary

    The most consistent behavioral change caused by olfactory bulbectomy (OBX) is a hyperemotional response to novel environmental stimuli. The aim of this study was to characterize the emotional behavior of OBX mice using the hole-board test. After the olfactory bulbs were lesioned, sham and OBX mice were housed in single cages for 14 days. The number of head-dips in the hole-board test in single-housed OBX mice was significantly greater than that in single-housed sham mice. The head-dipping behaviors in single-housed sham and OBX mice were reversed by treatment with diazepam, a typical benzodiazepine anxiolytic. (+/-)-8-Hydroxy-2-(di-n-propylamino) tetraline hydrobromide (8-OH-DPAT), a selective 5-HT(1A)-receptor agonist that has a non-benzodiazepine anxiolytic-like effect, and (+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethyl benzamide (SNC80), a delta-opioid-receptor agonist, also significantly reversed the number of head-dips in single-housed sham and OBX mice. In conclusion, we suggest that the single-housed OBX mice showed heightened emotional behavior (e.g., increase in head-dipping behavior) in the hole-board test. In addition, we suggest that the hyperemotional behavior characterized by head-dipping behavior in OBX mice was selectively reversed by benzodiazepine and non-benzodiazepine anxiolytics.

    DOI PubMed J-GLOBAL

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    38
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  • Effect of mexiletine on vincristine-induced painful neuropathy in mice.

    Junzo Kamei, Chihiro Nozaki, Akiyoshi Saitoh

    European journal of pharmacology   536 ( 1-2 ) 123 - 7  2006.04  [Refereed]  [International journal]

    Authorship:Lead author

     View Summary

    In the present study, we examined the effect of mexiletine on vincristine-induced thermal hyperalgesia in mice. Mice were intraperitoneally treated with vincristine at a dose of 0.05 mg/kg one day after the measurement of the pre-drug latency in the tail-flick test, and then treated with a dose of 0.125 mg/kg twice a week for 6 weeks. In vincristine-treated mice, a significant decrease in tail-flick latency developed at 6 weeks after treatment. Pretreatment with mexiletine, at doses of 3, 10 and 30 mg/kg, i.p., dose-dependently increased the tail-flick latency in vincristine-treated mice. A significant reduction of the tail-flick latency was observed when the tail-flick latency was examined 60 min after i.t. administration of NG-nitro-L-arginine methyl ester (L-NAME, 30 nmol), a nitric oxide synthase (NOS) inhibitor, in naive mice. This L-NAME-induced thermal hyperalgesia was dose-dependently attenuated by pretreatment with mexiletine (10 and 30 mg/kg, i.p.), 10 min before the injection of L-NAME. The duration of nociceptive behavioral response induced by fenvalerate, at a dose of 0.1 microg, i.t., was significantly increased by pretreatment with L-NAME (30 nmol, i.t.). Intrathecal pretreatment with L-arginine (300 pmol) significantly reversed the L-NAME-induced enhancement of fenvalerate-induced nociceptive responses. The present study demonstrates that systemic mexiletine can effectively attenuate vincristine-induced thermal hyperalgesia. Furthermore, these results suggest that blockade of nitric oxide-induced enhancement of nociceptive transmission, in which tetrodotoxin-resistant sodium channels play an important role, may participate in the antinociceptive effect of mexiletine on vincristine-induced thermal hyperalgesia.

    DOI PubMed J-GLOBAL

  • Characterization of the antinociceptive effects of oxycodone in diabetic mice.

    Chihiro Nozaki, Akiyoshi Saitoh, Junzo Kamei

    European journal of pharmacology   535 ( 1-3 ) 145 - 51  2006.03  [Refereed]  [International journal]

    Authorship:Lead author

     View Summary

    We investigated the antinociceptive efficacy of systemic and centrally injected oxycodone on thermal hyperalgesia in streptozotocin-induced diabetic mice. The antinociceptive response was assessed by recording the latency in the tail-flick test using the radiant heat from a 50-W projection bulb on the tail. The tail-flick latency in diabetic mice was significantly shorter than that in non-diabetic mice. Oral (p.o.) and i.t., but not i.c.v., administration of oxycodone prolonged the tail-flick latency in diabetic mice to a level that was considerably longer than the baseline latency in non-diabetic mice. However, morphine did not significantly inhibit the tail-flick response in diabetic mice. The antinociceptive effect of either p.o. or i.t. oxycodone in non-diabetic mice, but not in diabetic mice, was antagonized by pretreatment with a selective mu-opioid receptor antagonist, beta-funaltrexamine. In non-diabetic mice, pretreatment with a selective kappa-opioid receptor antagonist, nor-binaltorphimine, had no effect on the peak antinociceptive effect of either p.o. or i.t. oxycodone at 30 min after administration, however, it slightly but significantly reduced oxycodone-induced antinociception at 60 and 90 min after administration. On the other hand, pretreatment with nor-binaltorphimine practically abolished the antinociceptive effects of both p.o.- and i.t.-administered oxycodone in diabetic mice. Naltrindole, a selective delta-opioid receptor antagonist, had no effects on the antinociceptive effect of oxycodone in either non-diabetic or diabetic mice. These results suggest that the antinociceptive effects of oxycodone may be mediated by spinal kappa-opioid receptors in diabetic mice, whereas it may interact primarily with supraspinal and spinal mu-opioid receptors in non-diabetic mice.

    DOI PubMed J-GLOBAL

    Scopus

    31
    Citation
    (Scopus)
  • Antinociceptive effect of oxycodone in diabetic mice.

    Chihiro Nozaki, Akiyoshi Saitoh, Naoya Tamura, Junzo Kamei

    European journal of pharmacology   524 ( 1-3 ) 75 - 9  2005.11  [Refereed]  [International journal]

    Authorship:Lead author

     View Summary

    The effect of oxycodone on thermal hyperalgesia in streptozotocin-induced diabetic mice was examined. The antinociceptive response was assessed by recording the latency in the tail-flick test using the radiant heat from a 50-W projection bulb on the tail. The tail-flick latency in diabetic mice was significantly shorter than that in non-diabetic mice. When diabetic mice were treated with oxycodone (5 mg/kg, s.c.), the tail-flick latency in diabetic mice was prolonged to the level considerably longer than the baseline latencies of non-diabetic mice. However, s.c. administration of morphine (5 mg/kg) did not produce a significant inhibition of the tail-flick response in diabetic mice. Oxycodone, at doses of 1.25-5.0 mg/kg administered s.c., produced a dose-dependent increase in the tail-flick latencies in both diabetic and non-diabetic mice. The antinociceptive effect of oxycodone was antagonized by pretreatment with a selective delta-opioid receptor antagonist, beta-funaltrexamine (20 mg/kg, s.c.), in both non-diabetic and diabetic mice. In non-diabetic mice, pretreatment with a selective kappa-opioid receptor antagonist, nor-binaltorphimine (20 mg/kg, s.c.) had no effect on the peak antinociceptive effect of oxycodone observed 30 min after administration, however, it slightly but significantly reduced oxycodone-induced antinociception observed 60 and 90 min after administration. On the other hand, pretreatment with nor-binaltorphimine practically abolished the peak (30 min) and persistent (60 and 90 min) antinociceptive effects of oxycodone in diabetic mice. Naltrindole (35 mg/kg, s.c.), a selective delta-opioid receptor antagonist, had no effects on the antinociceptive effect of oxycodone in both non-diabetic and diabetic mice. These results suggest that the antinociceptive effects of oxycodone may be mediated by mu- and kappa-opioid receptors in diabetic mice, whereas it may interact primarily with mu-opioid receptors in non-diabetic mice.

    DOI PubMed J-GLOBAL

    Scopus

    39
    Citation
    (Scopus)

▼display all

Presentations

  • How do sleep cycles affect Cannabidiol users? ~生活スタイルはCBDの用途や効果にどう影響するか?

    野崎千尋, 潘辰語, 新田理恵, 柴田重信

    春の学術セミナー2023(日本臨床カンナビノイド学会) 

    Presentation date: 2023.04

  • カンナビノイドCB2受容体は神経炎症を抑制するとは限らない

    野崎千尋, Andreas Zimmer, 柴田重信

    日本薬理学会 

    Presentation date: 2022.12

    Event date:
    2022.11
    -
    2022.12
  • カンナビノイドの薬理:受容体が無いと我々の体はどうなってしまうのか

    野崎千尋  [Invited]

    日本臨床薬理学会 

    Presentation date: 2022.12

    Event date:
    2022.11
    -
    2022.12
  • Cannabinoid CB2 receptors have double-side role to peripheral neuroinflammation: What makes such a difference?

     [Invited]

    Presentation date: 2022.11

    Event date:
    2022.11
     
     
  • カンナビノイド受容体が持つ二面性~抑制か?賦活か?

    野崎千尋  [Invited]

    春の学術セミナー2022(日本臨床カンナビノイド学会) 

    Presentation date: 2022.03

  • Endocannabinoid System in the Neuroimmunology ~大麻が我々に何をもたらすか、もしくはドイツ研究生活の実際

    野崎千尋  [Invited]

    第23回BIRD脳科学セミナー 

    Presentation date: 2019.08

  • Endocannabinoid System in the Neuroimmunology ~大麻が我々に何をもたらすか、もしくはドイツ研究生活の実際

    野崎千尋  [Invited]

    平成31年度採用海外特別研究員オリエンテーション及びキャリアフォーラム 

    Presentation date: 2018.12

  • Involvement of leptin signaling in the development of cannabinoid CB2 receptor-dependent mirror image pain

    Chihiro Nozaki, Andreas Zimmer  [Invited]

    Presentation date: 2018.08

  • Genetic ablation of CB2 receptors enhances neuropathic pain development via boosted leptin signaling in peripheral nerves.

    Chihiro Nozaki, Astrid Markert, Andreas Zimmer

    The 90th Annual meeting of The Japanese Pharmacological Society 

    Presentation date: 2017.03

  • Contribution of endocannabinoid system on NTG-induced acute migraine-like symptoms

    Chihiro Nozaki, Andreas Zimmer  [Invited]

    18th German-Japanese Joint Symposium between the University of Bonn and Waseda University 

    Presentation date: 2016.09

  • Contribution of endocannabinoid system on NTG-induced acute migraine-like symptoms.

    Chihiro Nozaki, Astrid Markert, Andreas Zimmer

    International Narcotic Research Conference 

    Presentation date: 2016.07

  • Obesity and pain: Is there a link between leptin and endocannabinoid signaling?

    Chihiro Nozaki, Astrid Markert, Andreas Zimmer

    18th BONFOR-Symposium 

    Presentation date: 2015.04

  • Capsaicin-induced pain behavior is modulated in opioid receptors knockouts.

    Chihiro Nozaki, Claire Gaveriaux-Ruff C, David Reiss, Audrey Matifas, Brigitte Kieffer  [Invited]

    MOLECULAR TARGETS FOR NOVEL PAIN THERAPEUTICS: From basic research to clinical translation 

    Presentation date: 2010.09

  • Capsaicin-induced pain behavior is modulated by opioid receptors.

    Chihiro Nozaki, Claire Gaveriaux-Ruff C, David Reiss, Audrey Matifas, Brigitte Kieffer  [Invited]

    New Perspectives in Neuroscience: Joint Meeting of Young Italian and Japanese Neuroscientists 

    Presentation date: 2010.09

  • Modulation of capsaicin-induced pain behavior by opioid receptors

    Chihiro Nozaki, Claire Gaveriaux-Ruff, Brigitte Kieffer

    6ème Symposium du Réseau Recherche sur la Douleur 

    Presentation date: 2010.01

    Event date:
    2010.01
     
     
  • 糖尿病性有痛性神経障害に対する各種ATP受容体の関与

    野崎千尋, 亀井淳三

    第79回日本薬理学会年会 

    Presentation date: 2006.03

▼display all

Research Projects

  • 肥満が誘発する慢性炎症に関連する新たな分子・神経・免疫基盤の解明

    日本学術振興会  科学研究費助成事業

    Project Year :

    2020.04
    -
    2023.03
     

    野崎 千尋

     View Summary

    CB2受容体欠損マウスに1)LPS誘発全身性炎症および2)坐骨神経障害を誘導し、脾臓および坐骨神経組織における免疫細胞のプロファイルをフローサイトメーターを用いて解析するとともに、免疫組織化学染色を用いた解析も行った。その結果、特にLPS誘発全身性炎症モデルにおいて、LPSによって誘導される、脾臓のT細胞以外の細胞が、CB2の欠損により大きく変動することが解った。さらに末梢神経組織における免疫細胞の分取および解析方法を開発し、その手法を用いて坐骨神経障害モデルにおける坐骨神経組織の免疫細胞プロファイルの解析を行った。その結果、CB2欠損マウスの、特に非障害側組織において、特徴的なCD11bあるいはF4/80陽性マクロファージの存在が確認できた。

  • Role of endocannabinoid system on the modulation of migraine

    DFG  Eigene Stelle (Temporary PI)

    Project Year :

    2016.01
    -
    2018.12
     

    Chihiro Nozaki

  • Obesity and pain: Is there a link between leptin and endocannabinoid signaling?

    Bonfor  Fortsetzungsantrag fur Nachwuchsgruppen

    Project Year :

    2013.01
    -
    2014.12
     

    Chihiro Nozaki

Misc

  • The Use of an Amyloid beta Intracerebroventricular Model to Investigate the Interaction between Alzheimer‘s Disease and Circadian Dysfunction

    Lovell Lyndah, Nozaki Chihiro, Tahara Yu, Shibata Shigenobu

    Proceedings for Annual Meeting of The Japanese Pharmacological Society   96   3-B-SS14-2  2022.12

     View Summary

    There are 40 million people worldwide living with Alzheimer's Disease (AD), and by 2050 the prevalence is expected to increase to 150 million people, thus resulting in a 1 in 2 chance of having AD by the age of 85. An increase in amyloid-b plaques (Ab) and hyperphosphorylated tau are widely accepted as the core indicators of the disease. These indicators of AD onset and progression are becoming increasingly attributed to the disturbance of optimal sleep/wake cycles. Additionally, AD progression exacerbates normal sleep/wake cycles, resulting in a cyclical worsening of AD pathology, circadian rhythm, and cognitive dysfunction. By using an Ab intracerebroventricular (ICV) injection mouse model, mice can present an AD-like pathology within days to weeks after injection, allowing for the expedited examination of the disease. This model can serve as a tool to investigate the mechanism behind the disturbance of the biological clock and AD progression, and therefore find therapeutic targets to delay, prevent or cure the disease.

    DOI

  • Involvement of cannabinoid receptor type 2 (CB2) to dendritic cell population on inflammatory and allergic response

    Hosoki Haruka, Nozaki Chihiro, Furutani Akiko, Shibata Shigenobu

    Proceedings for Annual Meeting of The Japanese Pharmacological Society   96   1-B-SS06-5  2022.12

    Authorship:Corresponding author

     View Summary

    Cannabinoid receptor type 2 (CB2) is one of the major receptors for cannabis, which is expressed all over the body especially on the immune-related cells. It is considered that CB2 can work as a regulator in the immune system, particularly to suppress inflammatory responses in macrophages and microglias when activated. However no other immune cells have been studied whether and how they get modulated by CB2 activity. The objective of this experiment is to search for the other immune cell that can be affected by CB2 activity, and reveal the detailed mechanism of CB2-involved immune regulation.

    To characterize the CB2-regulated cells under the inflammatory state, we injected LPS (1 mg/kg, i.p.) to CB2 deficient mice (CB2-KO) and wild-type (WT) controls. Spleen has been harvested from these mice 2 hours after the LPS administration, and immunophenotyping by flow cytometry has been conducted. In this experiment, we found the particular increase of the type 2 classical dendritic cell (cDC2) population in LPS-treated CB2-KO. As past studies reported that cDC2 recruits helper T cells when the body is exposed to an allergen, we further induced allergic rhinitis by OVA sensitization to investigate in-vivo effect of cDC2 increase in CB2-KO and WT animals. As expected, CB2 deficiency resulted as the significant exacerbation of allergic symptoms compared to WT mice. These results suggest that CB2 activity may suppress the allergic response by the reduction of cDC2 recruitment. Pharmacological effect of CB2 agonists to these symptoms will be studied as the future experiment.

    DOI

  • カンナビノイド受容体が無くなると、我々の身体は一体どうなってしまうのか?

    野崎 千尋, Andreas Zimmer, 柴田 重信

    日本臨床薬理学会学術総会抄録集   43   3-C-S31-2  2022.12

    Authorship:Lead author, Corresponding author

     View Summary

    カンナビノイドが、今、熱い。その「大麻(カンナビス)」という言葉の響きもあってか、あるいは大麻が持つという様々な難治性疾患への治療効果を期待するからか、現在世界中で大麻由来成分=カンナビノイドを使った様々な製品が爆発的に流行している。現在のところ、他の医薬品などと比べて「確実にカンナビノイドの方が優れている」という科学的根拠はほぼ無いにも関わらず、である。とはいえ確かにある種の疾病の病態を改善し、QOLを上げるということは、例えば患者自身の経験として世に語られていたりする。彼らは一様に「エンドカンナビノイドシステムが鍵だ」というが、さて、一方でエンドカンナビノイドシステムがどこまで理解されているかは、また別の話であろう。エンドカンナビノイドシステム、日本語では一般的に内因性カンナビノイド系と呼ばれて来たシグナル伝達系は、大麻の活性成分が特異的に結合する2つのGタンパク質(Gi/o)共役型受容体CB1とCB2受容体と、これらの受容体の各々に対応する内因性リガンド、そしてこれらリガンド軍の生成酵素や分解酵素などから構築されている。長年CB1は脳や中枢神経系に、CB2は末梢の免疫系細胞に発現していると考えられて来たが、実際のところどちらの受容体も、ある程度の偏りはあるものの、全身に極めて広範に分布しており、それぞれの発現箇所で代謝系・神経系・免疫系など実に様々な生理機能を調節していることが、最近の研究で解って来た。さてここで1つお伺いしたい。これだけあちこちに広範に発現し、様々な生理機能の制御・調節を担うカンナビノイド受容体だが、ではこれらの受容体が無くなってしまったら、我々の身体は一体どうなってしまうのだろうか。つまり内因性カンナビノイド系が無いと、我々の身体には何がおきるのだろうか。我々はこの普遍的な問いに答えるべく、受容体を欠損させた遺伝子改変動物を用いて様々な検討を行ってきた。本講演ではその中でもCB1受容体の欠損が「加齢」や「肥満」に及ぼす影響、またCB2受容体の欠損が「感染症」や「慢性疼痛」にどのような影響を及ぼすかを、我々の最近の知見も併せて紹介する。

    DOI

  • Cellulose rich food induces intestinal disturbance, anxiety-like behavior and amygdalar dopaminergic hyperactivity in mice.

    Kaede Ito, Haraguchi Atsushi, Nozaki Chihiro, Shibata Shigenobu

    Proceedings for Annual Meeting of The Japanese Pharmacological Society   96   3-B-SS13-5  2022.12

     View Summary

    It is indicated that the intestinal environment affects the brain, which is known as the gut-brain axis. In fact, improvement of intestinal environment is reported to suppress anxiety-like behavior in mice model of depression and schizophrenia. However, its detailed mechanisms remain unclear, particularly in context of intestinal environment effects on emotion in non-disease mice. The object of this experiment is therefore to verify the effect of intestinal environment on anxiety-like behavior and its detailed physiological mechanisms.

    We previously found that cellulose rich food (AIN-93M) suppresses the production of short-chain fatty acid and exacerbate the intestinal condition. In the present study, we fed mice with AIN-93M to modify the intestinal environment, or the mouse chow that can maintain a favorable intestinal environment (MF). After 8-weeks feeding, AIN-93M-fed animals displayed the significant increase of marble-burying behavior compared to MF-fed group, suggesting that dysfunction of intestine lead by AIN-93M enhanced anxiety-like behavior. Furthermore, dopamine release as well as dopamine receptor expression has been increased in amygdala of AIN-93M fed mice but not in MF animals, indicating that enhanced anxiety-like behavior in AIN-93M animals is due to such modification of amygdalar dopaminergic system. 

    These results suggest that cellulose rich food may exacerbate intestinal environment, which may enhance the anxiety-like behavior and overactivation of dopaminergic system.

    DOI

  • Bipolar effect of cannabinoid CB2 receptors to peripheral neuroinflammation

    Nozaki Chihiro, Zimmer Andreas, Shibata Shigenobu

    Proceedings for Annual Meeting of The Japanese Pharmacological Society   96   3-B-O11-2  2022.12

    Authorship:Lead author, Corresponding author

     View Summary

    It is widely known that cannabinoid type 2 (CB2) receptor deficiency enhances neuroinflammation and pain development in the animal model of nerve injury-evoked neuropathic pain. We previously proposed the upregulated leptin signaling at the peripheral nerve as one of the underlying molecular mechanism, as nerve-injured CB2 receptor knockouts (CB2-KO) displayed robust upregulation of leptin receptors in both injured and non-injured nerve tissue. Those leptin receptors seemed to be expressed on the macrophages which is recruited to the nerve by the tissue injury, indicating the infiltration of leptin receptor-expressing macrophages. Thus, Due to these past results we also hypothesized that lack of CB2 receptor might also enhance the high fat diet (HFD)-induced peripheral neuroinflammation. However, surprisingly, CB2-KOs showed the significant resistance to the HFD-induced neuroinflammation. Namely, 5-week feeding of HFD induced substantial hypersensitivity in WT mice, while tactile sensitivity of HFD-fed CB2-KO remained intact. In the same animals, we further found the significant upregulation of infiltrated macrophages and chemokine receptor CXCR4 expression in HFD-fed WT animals, but not in either HFD-fed CB2 knockout mice or standard fat diet (SFD)-fed WT and CB2-KO controls. Based on these results, we will propose that CB2 receptors might have the bipolar regulatory role to chemokine receptor-mediated inflammatory response, which in the end enhance or inhibit the development of neuroinflammation depending on its cause.

    DOI

  • カンナビノイドCB2受容体の持つ二面性:レプチンシグナリングを介した末梢神経炎症調節機構に対する影響を中心に

    野崎千尋, Andreas Zimmer, 柴田重信

    Neuro2022    2022.06  [Refereed]

    Authorship:Lead author, Corresponding author

    Research paper, summary (national, other academic conference)  

  • Establishment of the novel method to culture primary neurons from aged rodent brain

    Yuya Kasai, Nozaki Chihiro, Shibata Shigenobu

    Proceedings for Annual Meeting of The Japanese Pharmacological Society   96   2-B-P-115  2022

    Authorship:Corresponding author

     View Summary

    Recent study showed that cannabinoid CB1 receptor-mediated signaling may take a huge role in age-related modification of brain function. CB1 deficient animals show significant cognitive deficit in old age, however they show better learning ability in young age. Even though the finding is surprising, the molecular mechanisms of such difference, especially for better learning in young age remains unknown mainly due to lack of suitable in-vivo/ex-vivo models. Here we will purpose to use the primary cultured neurons as the ex-vivo model of aging, which can be enabled with gentleMACS technology. This method is said to enable the primary cell culture from adult rodents but up to age of P60. In the present study we aimed to establish a method for primary culture of brain neurons using aged mice, which can be also used for knockout animals of CB1 receptors.

    We first tried to prepare the primary culture of brain neurons from neonatal (P7), young (P50) and mature (P105) mice. After 3-days of culture we could find that all of them survived well and start to extend their axons. Notably, P105 is twice an older age than previously reported suggesting that this method could be usable to evaluate the neuronal growth and cellular activity after the certain aging. Further, they could even survive for next 10-days with continuous axon growth. Using this method, we will further conduct the primary cell culture in knockout animals of CB1 as well as endocannabinoid producing enzyme DAGL-a to see the effect of endocannabinoid deficiency to the neuronal growth and cellular activity.

    DOI

  • Can Cannabidiol affect the peripheral circadian clockin PER2::LUC mice?

    Wang Hsiao Hsieh, Nozaki Chihiro, Shibata Shigenobu

    Proceedings for Annual Meeting of The Japanese Pharmacological Society   96   1-B-SS03-2  2022

    Authorship:Corresponding author

     View Summary

    Cannabidiol (CBD) is the second major cannabinoid which is often said to improveanxiety and sleep with no psychoactive effect. It is said that CBD can promotethe production of wake-related neurotransmitters such as dopamine. Further,co-injection of CBD and THC increased sleeping time in rats. However, no studyhas been done for the in-vivo effect of CBD to circadian clock. Present studyaimed to elucidate whether CBD can modify peripheral circadian rhythm.

    PER2::LUC knock-in female mice were used to determine the effect of CBD to theperipheral clock. Mice were divided into six groups: CBD isolate (99%crystalline) in MCT oil, CBD isolate in 5% EtOH/5% cremophor/water, andwater-soluble CBD nanopowder in water, with respective vehicle controls. Eachdrug was orally administered at ZT4 or ZT16 for three days, then PER2 geneexpression in the liver, kidney, and submandibular gland is observed by in-vivoimaging.

    We found that phase advance in the liver and the submandibular gland only happenswhen MCT or CBD in MCT (CBD/MCT) was administered at ZT4. However, the phaseadvance did not differ between the MCT and CBD/MCT groups. Furthermore, neitherthe vehicle nor the CBD affected the peripheral clock when administered atZT16. 

    This study suggested that not CBD but rather MCT oil affect the circadian clockin mice. As MCT oil is commonly used as a base for CBD products, we propose thatMCT might be the possible factor that affects the circadian clock and causerhythm improvement. Therefore further detailed studies on the effect of CBDproducts will be needed.

    DOI

  • 第26回 いかにして欧州でママさんチームリーダーとなったか

    野崎 千尋

    ファルマシア   57 ( 8 ) 768 - 769  2021  [Invited]

    Article, review, commentary, editorial, etc. (scientific journal)  

     View Summary

    博士号取得後フランスを経てドイツに流れつき、運良く研究費を得てチームリーダーにまでなった私の次の挑戦は「お母さんになること」だった。ドイツならではの医療制度および研究助成制度に助けられ倒して妊娠・出産・職場復帰までこぎつけた経緯を、そもそもなぜ欧州に飛ぶことになったのかも含めて紹介する。ご笑覧いただきたい。

    DOI CiNii

  • CB2 receptor deletion on myeloid cells elevates neuropathic pain development in mice

    Chihiro Nozaki, Elisa Nen, Andreas Zimmer

    50th International Narcotic Research Conference (INRC)    2019.07

    Authorship:Lead author

    Research paper, summary (international conference)  

  • Genetic ablation of CB2 receptors enhances neuropathic pain development via boosted leptin signaling in peripheral nerves

    Chihiro Nozaki, Andreas Zimmer

    12th Goettingen Meeting of the German Neuroscience Society    2017.03

    Authorship:Lead author

    Research paper, summary (international conference)  

  • Genetic ablation of CB2 receptors enhances neuropathic pain development via boosted leptin signaling in peripheral nerves

    Chihiro Nozaki, Nent Elisa, Markert Astrid, Zimmer Andreas

    JOURNAL OF PHARMACOLOGICAL SCIENCES   133 ( 3 ) S86 - S86  2017.03  [Refereed]

    Authorship:Lead author

    Research paper, summary (national, other academic conference)  

  • Nitroglycerin-induced migraine-like pain and trigeminal neuronal hyperactivity is enhanced by reduced CB1 receptor activity

    Chihiro Nozaki, Astrid Marker, Andreas Zimmer

    10th FENS Forum    2016.07  [Refereed]

    Authorship:Lead author

    Research paper, summary (international conference)  

  • Inhibition of FAAH reduces nitroglycerin-induced migraine-like pain and trigeminal neuronal hyperactivity in mice (vol 25, pg 1388, 2015)

    Chihiro Nozaki, Astrid Markert, Andreas Zimmer

    EUROPEAN NEUROPSYCHOPHARMACOLOGY   25 ( 11 ) 2186 - 2186  2015.11

    Authorship:Lead author, Corresponding author

    Other  

    DOI

  • Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes analgesia

    Raphael Weibel, Claire Gaveriaux-Ruff, Chihiro Nozaki, Xavier Nadal, Xavier C. Hever, Audrey Matifas, David Reissl, Dominique Filliol, John N. Wood, Rafael Maldonado, Brigitte L. Kieffer

    PHARMACOLOGICAL REPORTS   63 ( 1 ) 243 - 243  2011.01

    Research paper, summary (international conference)  

    DOI

  • Differential modulation of capsaicin-induced pain behavior by opioid receptors

    Chihiro Nozaki, Claire Gaveriaux-Ruff, Brigitte Kieffer

    Society for Neuroscience meeting (SfN)    2009.10

    Authorship:Lead author

    Research paper, summary (international conference)  

  • Antinociceptive effect of SP1-7 on thermal hyperalgesia in diabetic mice

    Chihiro Nozaki, Masahiro Ohsawa, Mathias Hallberg, Fred Nyberg, Junzo Kamei

    38th International Narcotic Research Conference (INRC)    2007.07

    Authorship:Lead author

    Research paper, summary (international conference)  

  • Role of cyclin-dependent kinase 5 (Cdk5) on capsaicin-induced cough reflex

    Shunsuke Hayashi, Junzo Kamei, Yoshiki Takahashi, Chihiro Nozaki

    JOURNAL OF PHARMACOLOGICAL SCIENCES   103   260P - 260P  2007

    Research paper, summary (international conference)  

  • 糖尿病マウスにおけるオキシコドン髄腔内投与による鎮痛作用

    野崎千尋, 斎藤顕宜, 亀井淳三

    第38回日本ペインクリニック学会    2006.07

    Authorship:Lead author

    Research paper, summary (national, other academic conference)  

  • The role of ATP receptor subtypes on the painful diabetic neuropathy in mice

    C Nozaki, J Kamei

    JOURNAL OF PHARMACOLOGICAL SCIENCES   100   67P - 67P  2006.03

    Authorship:Lead author

    Research paper, summary (national, other academic conference)  

  • Effects of fluvoxamine on allodynia- and anxiety-like behavior induced by sciatic nerve ligation in mice

    T Shimoi, A Saitoh, C Nozaki, N Hirose, J Kamei

    JOURNAL OF PHARMACOLOGICAL SCIENCES   100   250P - 250P  2006

    Research paper, summary (international conference)  

  • The antinociceptive effect of intrathecal (i.t.) oxycodone in diabetic mice

    Chihiro Nozaki, Akiyoshi Saitoh, Junzo Kamei

    World Congress of PAIN    2005.08  [Refereed]

    Authorship:Lead author

    Research paper, summary (international conference)  

  • Antinociceptive effect of fluvoxamine on thermal and mechanical nociception after peripheral nerve injury in the mouse

    Chihiro Nozaki, Akiyoshi Saitoh, Junzo Kamei

    36th International Narcotic research Conference (INRC)    2005.07

    Authorship:Lead author

    Research paper, summary (international conference)  

  • Effect of oxycodone on thermal allodynia in diabetic mice

    C Nozaki, N Tamura, A Saitoh, J Kamei

    JOURNAL OF PHARMACOLOGICAL SCIENCES   97   171P - 171P  2005.03

    Authorship:Lead author

    Research paper, summary (national, other academic conference)  

  • The antinociceptive effect of oxycodone in diabetic mice

    Chihiro Nozaki, Naoya Tamura, Akiyoshi Saitoh, Junzo Kamei

    International Symposium for opioid and pain-related peptide    2004.07

    Authorship:Lead author

    Research paper, summary (international conference)  

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Syllabus

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Teaching Experience

  • Introduction to Bioscience

    早稲田大学 理工学術院 国際理工学センター Major in Bioscience  

    2020.04
    -
    Now
     

  • Seminar on Problem Solving

    早稲田大学 理工学術院 国際理工学センター Major in Bioscience  

    2020.04
    -
    Now
     

  • Technical English for Scientific Research B

    早稲田大学 理工学術院 国際理工学センター Major in Bioscience  

    2020.04
    -
    Now
     

  • Neuroscience

    早稲田大学 理工学術院 国際理工学センター Major in Bioscience  

    2020.04
    -
    Now
     

  • Chemistry and Bioscience Laboratory

    早稲田大学 理工学術院 国際理工学センター Major in Bioscience  

    2020.04
    -
    Now
     

  • Science and Engineering Laboratory

    早稲田大学 理工学術院 国際理工学センター Major in Bioscience  

    2020.04
    -
    Now
     

  • Laboratory for Advanced Science and Engineering

    早稲田大学 理工学術院 国際理工学センター Major in Bioscience  

    2020.04
    -
    Now
     

  • Advanced Bioscience Seminar

    早稲田大学 理工学術院 国際理工学センター Major in Bioscience  

    2020.04
    -
    Now
     

  • Current Topics in Bioscience

    早稲田大学 理工学術院 国際理工学センター Major in Bioscience  

    2020.04
    -
    Now
     

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Sub-affiliation

  • Faculty of Science and Engineering   Graduate School of Advanced Science and Engineering

Research Institute

  • 2022
    -
    2024

    Waseda Research Institute for Science and Engineering   Concurrent Researcher

Internal Special Research Projects

  • 慢性疾患モデル動物の神経組織を元にした高品質な一次神経培養細胞の作成法の樹立

    2021  

     View Summary

    これまで困難とされてきた「発達期を抜けたマウスの脳細胞の初代培養方法の確立」を目指し、組織分散装置であるgentleMACSを導入して、1)初代培養に使用できるマウスの週齢および2)得られた細胞の生存期間の検討を行った。まず1)に関して、P7・P50・P110のマウスを用いて比較検討を行ったところ、何れの条件においても軸索の伸長を伴うカスパーゼ陰性神経細胞の存在が認められた。また2)に関して、少なくとも10日間は培養可能であることが確認できた。以上より、gentleMACSを利用することで「発達期を抜けたマウス由来の脳神経細胞」しかも「比較的長期間の培養に耐え得る細胞」を得られることが解った。

  • 片頭痛で認められる性差に対する内因性カンナビノイドの関与

    2020  

     View Summary

    新規嘱任でリソースがほぼ何もない状態からのスタートだったのに加え、コロナ禍で思うように実験研究が進められなかったこともあり、ひたすら来年以降の準備に勤しむことになってしまった。しかしこの助成金に加え2019年度末に採択された科研費も併せて、細胞分取装置を始めとする各種実験機材を取り揃えることができ、2021年度からは新たな研究を展開できる見込みである。本年は内藤記念財団の助成金にも挑戦したが不採択だったため、この新たに揃った研究機材でさらに成果を積み上げ、新たな助成金の採択に向けて挑戦して行きたいと考えている。