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

Supplemental Digital Content is Available in the Text.The escape of sensory axons from Wallerian degeneration is a risk factor for long-term hypersensitivity after crush injury to a peripheral nerve. 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.

Automated summary

This study investigates the neuropathology and sensory symptoms of a focal nerve crush injury. The results show that partial crush injury leads to the early return of pinprick sensitivity and persistent thermal and tactile hypersensitivity, which is not observed after a complete crush injury. Furthermore, the neuropathic pain caused by partial crush injury has distinct pathophysiology from that caused by complete nerve injury.