Neuropathic pain caused by miswiring and abnormal end organ targeting

TY - JOUR

T1 - Neuropathic pain caused by miswiring and abnormal end organ targeting

AU - Gangadharan, Vijayan

AU - Zheng, Hongwei

AU - Taberner, Francisco J

AU - Landry, Jonathan

AU - Nees, Timo A

AU - Pistolic, Jelena

AU - Agarwal, Nitin

AU - Männich, Deepitha

AU - Benes, Vladimir

AU - Helmstaedter, Moritz

AU - Ommer, Björn

AU - Lechner, Stefan G

AU - Kuner, Thomas

AU - Kuner, Rohini

N1 - © 2022. The Author(s).

PY - 2022/6

Y1 - 2022/6

N2 - 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 together1-3. 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 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 injury4-7-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.

AB - 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 together1-3. 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 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 injury4-7-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.

KW - Animals

KW - Chronic Pain/physiopathology

KW - Hyperalgesia/physiopathology

KW - Mechanoreceptors/pathology

KW - Mice

KW - Neuralgia/physiopathology

KW - Nociceptors/pathology

KW - Skin/innervation

U2 - 10.1038/s41586-022-04777-z

DO - 10.1038/s41586-022-04777-z

M3 - SCORING: Journal article

C2 - 35614217

VL - 606

SP - 137

EP - 145

JO - NATURE

JF - NATURE

SN - 0028-0836

IS - 7912

ER -