Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability

被引：141

作者：

Dawes, John M. ^{[1
]}

Weir, Greg A. ^{[1
]}

Middleton, Steven J. ^{[1
]}

Patel, Ryan ^{[2
]}

Chisholm, Kim I. ^{[3
]}

Pettingill, Philippa ^{[1
]}

Peck, Liam J. ^{[1
]}

Sheridan, Joseph ^{[1
]}

Shakir, Akila ^{[1
]}

Jacobson, Leslie ^{[1
]}

Gutierrez-Mecinas, Maria ^{[4
]}

Galino, Jorge ^{[1
]}

Walcher, Jan ^{[5
]}

Kuhnemund, Johannes ^{[5
]}

Kuehn, Hannah ^{[1
]}

Sanna, Maria D. ^{[1
]}

Lang, Bethan ^{[1
]}

Clark, Alex J. ^{[1
]}

Themistocleous, Andreas C. ^{[1
]}

Iwagaki, Noboru ^{[4
]}

West, Steven J. ^{[1
]}

Werynska, Karolina ^{[1
]}

Carroll, Liam ^{[1
]}

Trendafilova, Teodora ^{[1
]}

Menassa, David A. ^{[1
]}

Giannoccaro, Maria Pia ^{[1
]}

Coutinho, Ester ^{[1
]}

Cervellini, Ilaria ^{[1
]}

Tewari, Damini ^{[3
]}

Buckley, Camilla ^{[1
]}

Leite, M. Isabel ^{[1
]}

Wildner, Hendrik ^{[6
]}

Zeilhofer, Hanns Ulrich ^{[6
,7
]}

Peles, Elior ^{[8
]}

Todd, Andrew J. ^{[4
]}

McMahon, Stephen B. ^{[3
]}

Dickenson, Anthony H. ^{[2
]}

Lewin, Gary R. ^{[5
]}

Vincent, Angela ^{[1
]}

Bennett, David L. ^{[1
]}

机构：

[1] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England

[2] UCL, Dept Neurosci Physiol & Pharmacol, London WC1E 6BT, England

[3] Kings Coll London, Wolfson Ctr Age Related Dis, Neurorestorat Grp, London SE1 1UL, England

[4] Univ Glasgow, Coll Med Vet & Life Sci, Inst Neurosci & Psychol, Glasgow G12 8QQ, Lanark, Scotland

[5] Max Delbruck Ctr Mol Med, Mol Physiol Somat Sensat, Berlin, Germany

[6] Univ Zurich, Inst Pharmacol & Toxicol, Winterthurerstr 190, CH-8057 Zurich, Switzerland

[7] Swiss Fed Inst Technol, Inst Pharmaceut Sci, Vladimir Prelog Weg 10, CH-8093 Zurich, Switzerland

[8] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel

来源：

NEURON | 2018年 / 97卷 / 04期

基金：

英国惠康基金;

关键词：

NEUROPATHIC PAIN; CHANNELS; ABNORMALITIES; NEURONS; PROTEIN; TOUCH; ENCEPHALITIS; EXPRESSION; ANTIBODIES; THRESHOLD;

D O I：

10.1016/j.neuron.2018.01.033

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：806 / +

页数：27

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