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Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability.
Dawes, John M; Weir, Greg A; Middleton, Steven J; Patel, Ryan; Chisholm, Kim I; Pettingill, Philippa; Peck, Liam J; Sheridan, Joseph; Shakir, Akila; Jacobson, Leslie; Gutierrez-Mecinas, Maria; Galino, Jorge; Walcher, Jan; Kühnemund, Johannes; Kuehn, Hannah; Sanna, Maria D; Lang, Bethan; Clark, Alex J; Themistocleous, Andreas C; Iwagaki, Noboru; West, Steven J; Werynska, Karolina; Carroll, Liam; Trendafilova, Teodora; Menassa, David A; Giannoccaro, Maria Pia; Coutinho, Ester; Cervellini, Ilaria; Tewari, Damini; Buckley, Camilla; Leite, M Isabel; Wildner, Hendrik; Zeilhofer, Hanns Ulrich; Peles, Elior; Todd, Andrew J; McMahon, Stephen B; Dickenson, Anthony H; Lewin, Gary R; Vincent, Angela; Bennett, David L.
Afiliação
  • Dawes JM; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Weir GA; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Middleton SJ; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Patel R; Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK.
  • Chisholm KI; Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.
  • Pettingill P; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Peck LJ; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Sheridan J; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Shakir A; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Jacobson L; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Gutierrez-Mecinas M; Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
  • Galino J; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Walcher J; Molecular Physiology of Somatic Sensation, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
  • Kühnemund J; Molecular Physiology of Somatic Sensation, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
  • Kuehn H; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Sanna MD; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Lang B; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Clark AJ; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Themistocleous AC; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Iwagaki N; Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
  • West SJ; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Werynska K; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Carroll L; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Trendafilova T; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Menassa DA; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Giannoccaro MP; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Coutinho E; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Cervellini I; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Tewari D; Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.
  • Buckley C; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Leite MI; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Wildner H; Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
  • Zeilhofer HU; Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland; Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Vladimir-Prelog-Weg 10, 8093 Zurich, Switzerland.
  • Peles E; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
  • Todd AJ; Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
  • McMahon SB; Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.
  • Dickenson AH; Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK.
  • Lewin GR; Molecular Physiology of Somatic Sensation, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
  • Vincent A; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • Bennett DL; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK. Electronic address: david.bennett@ndcn.ox.ac.uk.
Neuron ; 97(4): 806-822.e10, 2018 02 21.
Article em En | MEDLINE | ID: mdl-29429934
ABSTRACT
Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2-/-) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2-/- mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células Receptoras Sensoriais / Imunoglobulina G / Dor Nociceptiva / Gânglios Espinais / Proteínas de Membrana / Proteínas do Tecido Nervoso Tipo de estudo: Etiology_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2018 Tipo de documento: Article
Texto completo
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XML
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Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células Receptoras Sensoriais / Imunoglobulina G / Dor Nociceptiva / Gânglios Espinais / Proteínas de Membrana / Proteínas do Tecido Nervoso Tipo de estudo: Etiology_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2018 Tipo de documento: Article