Abstract
Current rodent models of neuropathic pain produce pain hypersensitivity in almost all lesioned animals and not all identified experimental effects are pain specific. 18G needlestick-nerve-injury (NNI) to one tibial nerve of outbred Sprague-Dawley rats models the phenotype of Complex Regional Pain Syndrome (CRPS), a post-traumatic neuropathic pain syndrome, leaving roughly half of NNI rats with hyperalgesia. We compared endoneurial data from these divergent endophenotypes searching for pathological changes specifically associated with pain-behaviors. Tibial, sural, and common sciatic nerves from 12 NNI rats plus 10 nerves from sham-operated controls were removed 14 days post-surgery for morphometric analysis. PGP9.5(+) unmyelinated-fibers were quantitated in plantar hindpaw skin. Distal tibial nerves of NNI rats had endoneurial edema, 30% fewer axons, twice as many mast cells, and thicker blood-vessel walls than uninjured tibial nerves. However the only significant difference between nerves from hyperalgesic versus non-hyperalgesic NNI rats was greater endoneurial edema in hyperalgesic rats (p < 0.01). We also discovered significant axonal losses in uninjured ipsilateral sural nerves of NNI rats, demonstrating spread of neuropathy to nearby nerves formerly thought spared. Tibial and sural nerves contralateral to NNI had significant changes in endoneurial blood-vessels. Similar pathological changes have been identified in CRPS-I patients. The current findings suggest that severity of endoneurial vasculopathy and inflammation may correlate better with neuropathic pain behaviors than degree of axonal loss. Spread of pathological changes to nearby ipsilateral and contralateral nerves might potentially contribute to extraterritorial pain in CRPS.
Highlights
Chronic pain is a rare complication of damage to pain-system neurons, most often to nociceptive axons in peripheral nerves or roots
Tibial-needlestick nerve injury (NNI) overtly affected nearby ipsilesional sural nerves, these had not been penetrated by the needle (Figure 1, Table 2), producing statistically significant changes of similar magnitude to those detected within injured tibial nerves
NNI differs from other rat models of complex regional pain syndrome (CRPS)/post-traumatic neuralgia in causing a variable phenotype despite a highly standardized injury
Summary
Chronic pain is a rare complication of damage to pain-system neurons, most often to nociceptive axons in peripheral nerves or roots These long axons are vulnerable to traumatic or metabolic disconnection from their distant cell bodies, which can cause distal Wallerian degeneration. Rodent models have generated considerable molecular and pharmacological data about neuralgia, these have not translated well into new pain treatments (Lacroix-Fralish and Mogil, 2009). The efficiency of these models – almost all lesioned rats develop allodynia and/or hyperalgesia – might be one factor. Reporting the prevalences of specific phenotypes or outcomes is more useful
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