Person: Siegel, Sandra Marie
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Siegel
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Sandra Marie
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Siegel, Sandra Marie
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Publication Endoneurial pathology of the needlestick-nerve-injury model of Complex Regional Pain Syndrome, including rats with and without pain behaviors(Wiley-Blackwell, 2012) Klein, M.M.; Lee, Jeung Woon; Siegel, Sandra Marie; Downs, H.M.; Oaklander, AnneCurrent 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 bloodvessels. 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 contralesional nerves might potentially contribute to extraterritorial pain in CRPS.Publication Effects of distal nerve injuries on dorsal-horn neurons and glia: Relationships between lesion size and mechanical hyperalgesia(Elsevier BV, 2009) Lee, Jace; Siegel, Sandra Marie; Oaklander, AnnePenetrating limb injuries are common and usually heal without long-lasting effects, even when nerves are cut. However, rare nerve-injury patients develop prolonged and disabling chronic pain (neuralgia). When pain severity is disproportionate to severity of the inciting injury, physicians and insurers may suspect exaggeration and limit care or benefits, although the nature of the relationship between lesion-size and the development and persistence of neuralgia remains largely unknown. We compared cellular changes in the spinal dorsal-horn (the initial CNS pain-processing area) after partial or total tibial-nerve axotomies in male Sprague–Dawley rats to determine if these changes are proportional to the numbers of peripheral axons cut. Unoperated rats provided controls. Plantar hind-paw responses to touch, pin, and cold were quantitated bilaterally to identify hyperalgesic rats. We also compared data from nerve-injured rats with or without hyperalgesic responses to mechanical hind-paw stimulation to evaluate concordance between pain behaviors and dorsal-horn cellular changes. Hyperalgesia was no less prevalent or severe after partial than after total axotomy. L5 spinal-cord sections from rats killed 7 days postoperatively were labeled for markers of primary afferents (substance P calcitonin gene-related peptide isolectin B4, gamma aminobutyric acid, and glial fibrillary acidic protein), then labeled cells were stereologically quantitated in somatotopically defined dorsal-horn regions. Total axotomy reduced markers of primary afferents more than partial axotomy. In contrast, GABA-immunoreactive profiles were similarly reduced after both lesions, and in rats with sensory loss versus hyperalgesia. Numbers of GFAP-immunoreactive astrocytes increased independently of lesion size and pain status. Small nerve injuries can thus have magnified and disproportionate effects on dorsal-horn neurons and glia, perhaps providing a biological correlate for the disproportionate pain of post-traumatic neuralgias (including complex regional pain syndrome-I) that follow seemingly minor nerve injuries. However, the presence of similar dorsal-horn changes in rats without pain behaviors suggests that not all transcellular responses to axotomy are pain-specific.Publication Needlestick Distal Nerve Injury in Rats Models Symptoms of Complex Regional Pain Syndrome(Ovid Technologies (Wolters Kluwer Health), 2007) Siegel, Sandra Marie; Lee, Jeungchan; Oaklander, AnneBACKGROUND: Complex Regional Pain Syndrome (CRPS)-I consists of chronic limb pain and dysautonomia triggered by traumas that sometime seem too trivial to be causative. Several pathological studies have identified minor distal nerve injuries (DNIs) in CRPS-I patients, but retrospective studies cannot establish causality. Therefore, we, prospectively investigated whether DNIs are sufficient to cause CRPS-like abnormalities in animals. We used needlestick, a cause of human CRPS, to evaluate lesion-size effects. METHODS: Left tibial nerves of male Sprague–Dawley rats were transfixed once by 30G, 22G, or 18G needles. Unoperated and sham-operated rats provided controls. Hindpaw sensory function, edema, and posture were measured. RESULTS: At Day-7 postoperatively, thresholds for ipsilateral-hindpaw withdrawal from Semmes–Weinstein monofilaments were reduced by ≥51% in 0% of sham-operated controls; 67% of rats that received 18G-DNI, 88% that received 22G-DNI, and 89% that received 30G-DNI. Fifty-seven percent of all DNI rats had contralateral hindpaw “mirror” changes. The prevalence and severity of allodynia appeared independent of lesion size. Hyperalgesic responses to cold and pinprick applied to the plantar hindpaw were less common and were ipsilesional only, as was neurogenic hindpaw edema. Ipsilesional-only, tonic, dystonic-like hindpaw postures were evident in 42% of 18G-DNI, 6% of 22G-DNI, and no 30G-DNI or sham-operated control rats. The prevalence of postural abnormalities correlated with needle diameter (P = 0.001). Counting protein gene product 9.5-immunolabeled axons in skin biopsies from rats’ ipsilesional hindpaws demonstrated mean reductions of 0% after 30G-needlestick, 15% after 22G-needlestick, and 26% after 18G-needlestick, which closely reproduces the 29% mean epidermal neurite losses of CRPS-I patients. CONCLUSIONS: Needlestick DNI models several clinical and pathological features of human CRPS and provides direct prospective evidence that even minor DNI can cause CRPS-like abnormalities in rats.