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.

中文翻译：

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CASPR2 的免疫或遗传介导的破坏由于初级传入兴奋性增强而导致疼痛超敏反应。

接触素相关蛋白样 2 (CASPR2) 的人类自身抗体通常与神经性疼痛有关，而 CASPR2 突变与自闭症谱系障碍有关，其中感觉功能障碍越来越被人们认识。人类 CASPR2 自身抗体在注射到小鼠体内时会受到外周限制，并在没有神经损伤的情况下导致机械性疼痛相关的超敏反应。因此，我们研究了 CASPR2 调节伤害感受功能的机制。缺乏 CASPR2 (Cntnap2-/-) 的小鼠表现出对有害机械刺激、热和 algogen 增强的疼痛相关超敏反应。在 Cntnap2-/- 小鼠中，主要传入兴奋性和随后的背角内的伤害性传递都增加了。CASPR2 的免疫或遗传介导的消融通过调节体膜上的 Kv1 通道表达以细胞自主方式增强了 DRG 神经元的兴奋性。这是自身免疫性周围神经性疼痛障碍被动转移的第一个例子，并证明 CASPR2 在调节细胞内在背根神经节 (DRG) 神经元兴奋性中起关键作用。