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 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.
Item Type: | Journal article |
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Form of publication: | Publisher's Version |
Faculties: | History and Art History > Department of Art History > Art History |
Subjects: | 000 Computer science, information and general works > 004 Data processing computer science 600 Technology > 610 Medicine and health |
URN: | urn:nbn:de:bvb:19-epub-107322-7 |
ISSN: | 0028-0836 |
Language: | English |
Item ID: | 107322 |
Date Deposited: | 04. Oct 2023, 13:52 |
Last Modified: | 28. May 2024, 12:28 |