Neuropathic pain caused by mis-wiring and abnormal end organ targeting. Neuropathic pain caused by mis-wiring and abnormal end organ targeting

Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as loss of sensation in the areas where injured and non-injured nerves comingle1-3. Mechanisms disambiguating these mixed and paradoxical symptoms are unknown. Here, we longitudinally and non-invasively imaged genetically-labelled populations of fibres sensing noxious stimuli (nociceptors) and gentle touch (low threshold afferents) peripherally in the skin for longer than 10 months post-nerve injury while simultaneously tracking pain-related behaviour in the same mice. Fully denervated skin areas initially lost sensation, gradually recovered normal sensitivity and unexpectedly developed marked allodynia and aversion to gentle touch several months post-injury. This reinnervation-associated 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. In contrast, low threshold afferents, which normally mediate touch sensation as well as allodynia in intact nerve territories post- injury4-7, failed to reinnervate, leading to an aberrant state of apposition of tactile end organs, such as Meissner corpuscles, with nociceptors alone. Genetic ablation of nociceptors fully abrogated reinnervation allodynia. Our results thus demonstrate the emergence of a novel form of chronic neuropathic pain driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation, providing a mechanistic framework for the paradoxical sensory manifestations observed clinically and imposing a heavy burden on patients.

神经损伤可引发慢性疼痛、轻触诱发痛（allodynia），并在损伤神经与未损伤神经混杂的区域造成感觉丧失[1-3]。目前，阐明这类混杂且矛盾的临床症状的潜在机制仍不明晰。本研究在神经损伤后超过10个月的周期内，对小鼠皮肤外周的两类基因标记神经纤维开展了纵向无创成像：一类为感知伤害性刺激的伤害性感受器（nociceptors），另一类为感知轻触的低阈值传入纤维（low threshold afferents），同时同步追踪同一只小鼠的痛相关行为。结果显示，完全去神经支配的皮肤区域最初会丧失感觉，随后逐渐恢复正常敏感性，但在损伤数月后却意外出现显著的轻触诱发痛与轻触厌恶。这种与再神经支配相关的神经性疼痛，由向去神经支配区域发芽的伤害性感受器介导：这些伤害性感受器精准复刻了初始的神经支配模式，受血管引导，在皮肤内形成不规则的终末连接，且激活阈值降低，模拟了低阈值传入纤维的功能特性。与之相反，既往研究[4-7]表明可介导损伤后完整神经区域触觉与轻触诱发痛的低阈值传入纤维，无法完成再神经支配，进而导致仅由伤害性感受器与触觉终末器官（如迈斯纳小体（Meissner corpuscles））形成异常对接状态。对伤害性感受器进行基因敲除可完全消除再神经支配相关的轻触诱发痛。综上，本研究结果揭示了一种新型慢性神经性疼痛，其由再神经支配过程中的结构可塑性、异常终末连接以及伤害性感受器功能异常所驱动，该发现为临床中观察到的矛盾性感觉表现提供了机制框架，同时也阐明了此类病症给患者带来的沉重疾病负担。