Background & Aims
Preclinical pain studies have struggled in its translatability into clinical management of chronic pain patients. Reconsideration of established rodent pain models and assessments of pain may be opportunities for improvement.1,2 Spinal nerve ligation (SNL), spared nerve injury (SNI), and chronic constriction injury (CCI) are three of the most common models for nerve injury-induced neuropathic pain.1 While all three models produce localized pain in rodent, they also result in motor defects in the affected limb.3–7 Common human neuropathic pain such as radicular pain and postherpetic neuralgia are not associated with motor deficiencies. Moreover, pain in rodents is assessed by behavioral observations – a motor-dependent output. We developed a pure sensory neuropathic pain model which lacks motor deficits to improve face validity to human pain conditions and to avoid interference with pain behavior assays – herein referred to as the saphenous-sural nerve injury (SSNI) model.
Methods
The SSNI model was established by ligating then transecting the sensory saphenous and sural nerves under anesthesia. SNL8, spared tibial nerve injury9, spared sural nerve injury10, and CCI11 were performed as previously reported. Mechanical hypersensitivity was assessed by Von Frey filaments and by light brush. Spontaneous pain behavior in an observer-free, free roaming environment was assessed by recording and analysis using the Blackbox apparatus12. Motor function was assessed by rotarod, position of the hind limb on landing from a height (landing foot motion assay), and extent of footdrop with ambulation (walking dorsal footprint assay). Nerve injury was detected by ATF3 immunofluorescent staining in fixed dorsal root ganglion (DRG) and spinal cord (SC) sections.
Results
SSNI induced severe evoked mechanical hypersensitivity in both males and female mice as early as one day after injury and persisted for at least 28 days. Mechanical hypersensitivity was detected in response to punctate and dynamic mechanical stimuli. SSNI also induced spontaneous pain behavior as mice after SSNI exhibited avoidance of weightbearing on the hind limb ipsilateral to the nerve injury. SSNI did not induce any motor impairments, in contrast to deficits exhibited in the SNL, spared tibial nerve, spared sural nerve, and CCI models. Nerve injury marker, ATF3, was induced in the lumbar DRG ipsilateral to the injury in all nerve injury models including SSNI. ATF3 was also induced in the motor neurons in the lumbar ventral horn of established nerve injury models, while it was notably absent in the SSNI group.
Conclusions
We described a novel mouse model of exclusively sensory nerve injury for the study of pain. By targeting the purely sensory saphenous and sural nerves, our SSNI model induced rapid and persistent pain behavior across multiple domains of evoked and spontaneous pain assays. Additionally, we provided evidence of nerve injury by induction of the nerve injury marker, ATF3, in the primary sensory neurons in the DRG. The keystone feature of this model is the lack of motor involvement. In established models of nerve injury, ATF3 was detected in the motor neuron cell bodies with surrounding gliosis in the ventral horn of the SC. However, this was absent in the SSNI model further supporting the lack of injury to the motor circuitry. The SSNI model is an important tool to advance preclinical modeling of pain and allows for the confident interpretation of behaviors as exclusively due to the sensory impact from the pain model.
References
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Presenting Author
Paul Su
Poster Authors
Paul Su
MD
University of California San Francisco
Lead Author
Topics
- Mechanisms: Biological-Molecular and Cell Biology