小柯机器人

错误连接和终末器官靶向异常可引起神经病理性疼痛
2022-05-29 14:00

德国海德堡大学Rohini Kuner研究组发现错误连接和终末器官靶向异常可引起神经性疼痛。2022年5月25日出版的《自然》杂志在线发表了这项成果。

研究人员在神经损伤后超过10个月的时间里,以纵向和非侵入性地方式对基因标记的纤维群进行成像,这些纤维群在皮肤周围感知有害刺激(伤害感受器)和轻柔触摸(低阈值传入),同时跟踪这些小鼠与疼痛相关的行为。完全去神经支配的皮肤区域最初失去感觉,逐渐恢复正常敏感性,并在受伤几个月后出现明显的异常性疼痛和对轻触的厌恶。这种神经再支配引起的神经性疼痛与伤害感受器有关,这些伤害感受器延伸到去神经支配的区域,精确地再现神经支配的初始模式,由血管引导,在皮肤中显示出不规则的终端连接,并降低了模拟低阈值传入的激活阈值。

相比之下,低阈值传入神经(通常在损伤后完整神经区域中介导触觉以及异常性疼痛)没有重新建立神经支配,导致仅具有伤害感受器的迈斯纳小体等触觉末端器官受异常神经支配。敲除与伤害感受器有关的基因完全消除了神经再支配异常性疼痛。因此,该研究结果揭示了一种慢性神经性疼痛的发生机制,这种疼痛是由结构可塑性、异常末端连接和神经再支配过程中伤害感受器受损造成的,并为在临床观察到的对病人产生沉重负担的矛盾感觉提供了机制框架。

据了解,神经损伤会导致慢性疼痛和对轻柔触摸的过度敏感(异常性疼痛)以及受伤和未受伤神经聚集区域的感觉丧失。改善这些混合和矛盾症状的机制尚不清楚。

附:英文原文

Title: Neuropathic pain caused by miswiring and abnormal end organ targeting

Author: Gangadharan, Vijayan, Zheng, Hongwei, Taberner, Francisco J., Landry, Jonathan, Nees, Timo A., Pistolic, Jelena, Agarwal, Nitin, Mnnich, Deepitha, Benes, Vladimir, Helmstaedter, Moritz, Ommer, Bjrn, Lechner, Stefan G., Kuner, Thomas, Kuner, Rohini

Issue&Volume: 2022-05-25

Abstract: Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as a loss of sensation in the areas in which injured and non-injured nerves come together1,2,3. The mechanisms that disambiguate these mixed and paradoxical symptoms are unknown. Here we longitudinally and non-invasively imaged genetically labelled populations of fibres that sense noxious stimuli (nociceptors) and gentle touch (low-threshold afferents) peripherally in the skin for longer than 10months after nerve injury, while simultaneously tracking pain-related behaviour in the same mice. Fully denervated areas of skin initially lost sensation, gradually recovered normal sensitivity and developed marked allodynia and aversion to gentle touch several months after injury. This reinnervation-induced neuropathic pain involved nociceptors that sprouted into denervated territories precisely reproducing the initial pattern of innervation, were guided by blood vessels and showed irregular terminal connectivity in the skin and lowered activation thresholds mimicking low-threshold afferents. By contrast, low-threshold afferents—which normally mediate touch sensation as well as allodynia in intact nerve territories after injury4,5,6,7—did not reinnervate, leading to an aberrant innervation of tactile end organs such as Meissner corpuscles with nociceptors alone. Genetic ablation of nociceptors fully abrogated reinnervation allodynia. Our results thus reveal the emergence of a form of chronic neuropathic pain that is driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation, and provide a mechanistic framework for the paradoxical sensory manifestations that are observed clinically and can impose a heavy burden on patients.

DOI: 10.1038/s41586-022-04777-z

Source: https://www.nature.com/articles/s41586-022-04777-z

 

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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