TY - JOUR
T1 - Long-term tactile hypersensitivity after nerve crush injury in mice is characterized by the persistence of intact sensory axons
AU - Kim, Hyoung Woo
AU - Shim, Sang Wook
AU - Zhao, Anna Mae
AU - Roh, Dahee
AU - Han, Hye Min
AU - Middleton, Steven J.
AU - Kim, Wheedong
AU - Chung, Sena
AU - Johnson, Errin
AU - Prentice, John
AU - Tacon, Mike
AU - Koel-Simmelink, Marleen J. A.
AU - Wieske, Luuk
AU - Teunissen, Charlotte E.
AU - Bae, Yong Chul
AU - Bennett, David L. H.
AU - Rinaldi, Simon
AU - Davies, Alexander J.
AU - Oh, Seog Bae
N1 - Funding Information: The authors thank Chan Hee Won, our previous laboratory assistant, for critical assistance in behavior experiments, Dr. Dae-Hyun Roh at the Kyung Hee University for assistance with rotor-rod testing, and Dr. Yong Ho Kim at the Gachon University and Dr. Pa Reum Lee at the Korea Institute of Science and Technology for assistance with nerve tracing. The authors thank Hyoung Yon Kim at the Korea University for statistical support on single-axon analysis and Dr. Shuaiwei Wang for assistance with behavioral experiments. The authors thank Kyle Hallett and Joseph Tacon at the Oxford Departments of Oncology and Physics, respectively, for their assistance with the haemostat customisation and quality control measurements. The authors also thank Charlotte Melia and the team at the Sir William Dunn School of Pathology Bioimaging Facility for their assistance with TEM. The authors are especially grateful to Dr. Hwan Tae Park, Dr. Jung Eun Shin, Dr. Ahmet Hoke, Dr. Annina Schmid, Dr. Alban Latremoliere, and Dr. Michael Costigan for helpful advice and discussion on peripheral nerve anatomy and analysis and the partial crush injury model. This research was supported by the National Research Foundation of Korea grants (NRF-2018R1A5A2024418 and NRF-2021R1A2C3003334) funded by the Korean government MSIT (Ministry of Science and ICT) to S. B. Oh, a UKRI Future Leaders Fellowship grant (MR/V02552X/1) to A. J. Davies, Medical Research Council UK (MR/P008399/1) to S. Rinaldi, and Medical Research Council UK (MR/T020113/1) to D. L. H. Bennett. A. J. Davies also receives support from the Children's Cancer and Leukaemia Group (CCLG) (CCLGA 2022 05). For the purpose of Open Access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript (AAM) version arising from this submission. Publisher Copyright: © 2023 Lippincott Williams and Wilkins. All rights reserved.
PY - 2023/10/1
Y1 - 2023/10/1
N2 - Traumatic peripheral nerve injuries are at high risk of neuropathic pain for which novel effective therapies are urgently needed. Preclinical models of neuropathic pain typically involve irreversible ligation and/or nerve transection (neurotmesis). However, translation of findings to the clinic has so far been unsuccessful, raising questions on injury model validity and clinically relevance. Traumatic nerve injuries seen in the clinic commonly result in axonotmesis (ie, crush), yet the neuropathic phenotype of "painful" nerve crush injuries remains poorly understood. We report the neuropathology and sensory symptoms of a focal nerve crush injury using custom-modified hemostats resulting in either complete ("full") or incomplete ("partial") axonotmesis in adult mice. Assays of thermal and mechanically evoked pain-like behavior were paralleled by transmission electron microscopy, immunohistochemistry, and anatomical tracing of the peripheral nerve. In both crush models, motor function was equally affected early after injury; by contrast, partial crush of the nerve resulted in the early return of pinprick sensitivity, followed by a transient thermal and chronic tactile hypersensitivity of the affected hind paw, which was not observed after a full crush injury. The partially crushed nerve was characterized by the sparing of small-diameter myelinated axons and intraepidermal nerve fibers, fewer dorsal root ganglia expressing the injury marker activating transcription factor 3, and lower serum levels of neurofilament light chain. By day 30, axons showed signs of reduced myelin thickness. In summary, the escape of small-diameter axons from Wallerian degeneration is likely a determinant of chronic pain pathophysiology distinct from the general response to complete nerve injury.
AB - Traumatic peripheral nerve injuries are at high risk of neuropathic pain for which novel effective therapies are urgently needed. Preclinical models of neuropathic pain typically involve irreversible ligation and/or nerve transection (neurotmesis). However, translation of findings to the clinic has so far been unsuccessful, raising questions on injury model validity and clinically relevance. Traumatic nerve injuries seen in the clinic commonly result in axonotmesis (ie, crush), yet the neuropathic phenotype of "painful" nerve crush injuries remains poorly understood. We report the neuropathology and sensory symptoms of a focal nerve crush injury using custom-modified hemostats resulting in either complete ("full") or incomplete ("partial") axonotmesis in adult mice. Assays of thermal and mechanically evoked pain-like behavior were paralleled by transmission electron microscopy, immunohistochemistry, and anatomical tracing of the peripheral nerve. In both crush models, motor function was equally affected early after injury; by contrast, partial crush of the nerve resulted in the early return of pinprick sensitivity, followed by a transient thermal and chronic tactile hypersensitivity of the affected hind paw, which was not observed after a full crush injury. The partially crushed nerve was characterized by the sparing of small-diameter myelinated axons and intraepidermal nerve fibers, fewer dorsal root ganglia expressing the injury marker activating transcription factor 3, and lower serum levels of neurofilament light chain. By day 30, axons showed signs of reduced myelin thickness. In summary, the escape of small-diameter axons from Wallerian degeneration is likely a determinant of chronic pain pathophysiology distinct from the general response to complete nerve injury.
KW - Axonotmesis
KW - Chronic pain
KW - Mechanical allodynia
KW - Neuropathic pain
KW - Partial crush
KW - Peripheral nerve injury
KW - Preclinical pain model
KW - Wallerian degeneration
UR - http://www.scopus.com/inward/record.url?scp=85171393282&partnerID=8YFLogxK
U2 - https://doi.org/10.1097/j.pain.0000000000002937
DO - https://doi.org/10.1097/j.pain.0000000000002937
M3 - Article
C2 - 37366595
SN - 0304-3959
VL - 164
SP - 2327
EP - 2342
JO - Pain
JF - Pain
IS - 10
ER -