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Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability

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Item Type:Article
Title:Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability
Creators Name:Dawes, J.M. and Weir, G.A. and Middleton, S.J. and Patel, R. and Chisholm, K.I. and Pettingill, P. and Peck, L.J. and Sheridan, J. and Shakir, A. and Jacobson, L. and Gutierrez-Mecinas, M. and Galino, J. and Walcher, J. and Kühnemund, J. and Kuehn, H. and Sanna, M.D. and Lang, B. and Clark, A.J. and Themistocleous, A.C. and Iwagaki, N. and West, S.J. and Werynska, K. and Carroll, L. and Trendafilova, T. and Menassa, D.A. and Giannoccaro, M.P. and Coutinho, E. and Cervellini, I. and Tewari, D. and Buckley, C. and Leite, M.I. and Wildner, H. and Zeilhofer, H.U. and Peles, E. and Todd, A.J. and McMahon, S.B. and Dickenson, A.H. and Lewin, G.R. and Vincent, A. and Bennett, D.L.
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.
Keywords:DRG, Sensory Neuron, Pain, CASPR2, CNTNAP2, Autism, Autoantibody, Mechanosensation, Voltage-Gated Potassium Channel, Kv1, Animals, Mice
Source:Neuron
ISSN:0896-6273
Publisher:Cell Press (U.S.A.)
Volume:97
Number:4
Page Range:806-822.e10
Date:21 February 2018
Official Publication:https://doi.org/10.1016/j.neuron.2018.01.033
PubMed:View item in PubMed

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