Neuropathic pain caused by miswiring and abnormal end organ targeting

• DOI: 10.1038/s41586-022-04777-z
• Publication Date: 2022-05-25T16:04:02Z
• Authors: Vijayan Gangadharan; Hongwei Zheng; Francisco J. Tabe...; Jonathan Landry; Timo A. Nees; Jelena Pistolic; Nitin Agarwal; Deepitha Männich; Vladimir Benes; Moritz Helmstaedter; Björn Ommer; Stefan G. Lechner; Thomas Kuner; Rohini Kuner
• Keywords: Mice; Hyperalgesia; Animals; Neuralgia; Nociceptors; Chronic Pain; Mechanoreceptors; Article; Skin

Abstract Nerve injury leads to chronic pain and exaggerated sensitivity gentle touch (allodynia) as well a loss of sensation in the areas which injured non-injured nerves come together 1–3 . The mechanisms that disambiguate these mixed paradoxical symptoms are unknown. Here we longitudinally non-invasively imaged genetically labelled populations fibres sense noxious stimuli (nociceptors) (low-threshold afferents) peripherally skin for longer than 10 months after nerve injury, while simultaneously tracking pain-related behaviour same mice. Fully denervated initially lost sensation, gradually recovered normal developed marked allodynia aversion several injury. This reinnervation-induced neuropathic involved nociceptors sprouted into territories precisely reproducing initial pattern innervation, were guided by blood vessels showed irregular terminal connectivity lowered activation thresholds mimicking low-threshold afferents. By contrast, afferents—which normally mediate intact 4–7 —did not reinnervate, leading an aberrant innervation tactile end organs such Meissner corpuscles with alone. Genetic ablation fully abrogated reinnervation allodynia. Our results thus reveal emergence form is driven structural plasticity, abnormal malfunction during reinnervation, provide mechanistic framework sensory manifestations observed clinically can impose heavy burden on patients.