Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
Max Planck Institute for Brain Research, Frankfurt am Main, Germany.
Nature. 2022 Jun;606(7912):137-145. doi: 10.1038/s41586-022-04777-z. Epub 2022 May 25.
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 together. 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 10 months 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 injury-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.
神经损伤会导致慢性疼痛和对轻柔触摸的过度敏感（感觉异常），以及受伤和未受伤神经交汇区域的感觉丧失。目前尚不清楚区分这些混合和矛盾症状的机制。在这里，我们在神经损伤后 10 个多月的时间里，对感觉有害刺激（伤害感受器）和轻柔触摸（低阈值传入纤维）的基因标记纤维进行了纵向和非侵入性成像，同时跟踪了同一批小鼠的与疼痛相关的行为。皮肤的完全去神经区域最初失去感觉，逐渐恢复正常敏感性，并在受伤后数月出现明显的感觉异常和对轻柔触摸的回避。这种再神经支配诱导的神经病理性疼痛涉及到伤害感受器，它们精确地在去神经区域中发芽，重现了最初的神经支配模式，受血管引导，并在皮肤中表现出不规则的末端连接性，激活阈值降低，模拟低阈值传入纤维。相比之下，低阈值传入纤维——在损伤后的完整神经区域通常介导触摸感觉以及感觉异常——并没有再支配，导致触觉终末器官（如梅克尔小体）的异常支配，只有伤害感受器。伤害感受器的基因消融完全消除了再神经支配的感觉异常。因此，我们的研究结果揭示了一种慢性神经病理性疼痛的出现形式，这种疼痛是由再神经支配过程中的结构可塑性、异常末端连接性和伤害感受器功能障碍驱动的，并为临床上观察到的矛盾性感觉表现提供了一个机制框架，这些表现会给患者带来沉重的负担。
