Long-term tactile hypersensitivity after nerve crush injury in mice is characterized by the persistence of intact sensory axons

Abstract

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.

Myelinated peripheral axons are more vulnerable to mechanical trauma in a model of enlarged axonal diameters

“…Our data are also in agreement with a recent report that a partial nerve crush injury spares small-diameter axons from degenerating and preserves afferent fiber innervation with the skin. The observations likely represent a risk for the development of neuropathic pain, a clinical condition for which effective therapies are not existent (Kim et al, 2023). Thus, mild compression injury or partial crush models may be well suited to model particular human peripheral nerve injury types and have the potential to support the translation from animal to the clinic.…”

Strategies for Treating Traumatic Neuromas with Tissue-Engineered Materials

“…It involves the interruption or severe destruction of axons following peripheral nerve injury, with antegrade degeneration potentially occurring in the distal segment of the injury. However, the surrounding supporting structures, particularly the endoneurium, remain intact [18]. During regeneration, axons endeavor to grow across the injury site, guided by the endoneurial canal.…”