Development of a Duration Threshold for Modulating Evoked Neuronal Responses After Nerve Root Compression Injury

Nicholson, Kristen; Quindlen, Julia C.; Winkelstein, Beth A.

doi:10.4271/2011-22-0001

Cited by 7 publications

(28 citation statements)

References 69 publications

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“…The first set of studies characterize the time course of BSCB breakdown following painful and non-painful nerve root compression in the rat and investigate potential relationships between peripheral inflammation and pain at times of BCSB breakdown. Two durations of nerve root compression were administered in the rat: 15-minutes because it has been shown to induce sustained nociception and 3-minutes to serve as a loading control in which the nerve root undergoes injury, but pain-related behaviors do not develop (40,41). BSCB permeability was investigated by immunolabeling the spinal cord for IgG, a blood protein that is not present in the CNS under normal conditions, at day 1 and day 7.…”

Section: Methodsmentioning

confidence: 99%

“…Fixed C7 spinal cord sections were fluorescently immunolabeled for rat IgG AlexaFluor 568 (1:200; Life Technologies). Images of the bilateral dorsal horns (n=3-6 sections/rat) were analyzed using a customized densitometry MATLAB code to quantify IgG labeling, which was then compared to labeling in tissue from naïve rats (39,40,43). Normalized percent IgG was compared between groups on days 1 and 7 using a two-way ANOVA (group × day) with Tukey’s HSD test.…”

Section: Methodsmentioning

confidence: 99%

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Salmon-derived thrombin inhibits development of chronic pain through an endothelial barrier protective mechanism dependent on APC

et al. 2016

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Many neurological disorders are initiated by blood-brain barrier breakdown, which potentiates spinal neuroinflammation and neurodegeneration. Peripheral neuropathic injuries are known to disrupt the blood-spinal cord barrier (BSCB) and to potentiate inflammation. But, it is not known whether BSCB breakdown facilitates pain development. In this study, a neural compression model in the rat was used to evaluate relationships among BSCB permeability, inflammation and pain-related behaviors. BSCB permeability increases transiently only after injury that induces mechanical hyperalgesia, which correlates with serum concentrations of pro-inflammatory cytokines, IL-7, IL-12, IL-1α and TNF-α. Mammalian thrombin dually regulates vascular permeability through PAR1 and activated protein C (APC). Since thrombin protects vascular integrity through APC, directing its affinity towards protein C, while still promoting coagulation, might be an ideal treatment for BSCB-disrupting disorders. Salmon thrombin, which prevents the development of mechanical allodynia, also prevents BSCB breakdown after neural injury and actively inhibits TNF-α-induced endothelial permeability in vitro, which is not evident the case for human thrombin. Salmon thrombin’s production of APC faster than human thrombin is confirmed using a fluorogenic assay and APC is shown to inhibit BSCB breakdown and pain-related behaviors similar to salmon thrombin. Together, these studies highlight the impact of BSCB on pain and establish salmon thrombin as an effective blocker of BSCB, and resulting nociception, through its preferential affinity for protein C.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Salmon-derived thrombin inhibits development of chronic pain through an endothelial barrier protective mechanism dependent on APC

et al. 2016

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“…Surgical procedures were performed as previously described [15, 16]. Briefly, adult male Holtzman rats were anesthetized using inhalation isoflurane anesthesia and the right C6 and C7 vertebrae were cleared of the paraspinal muscle.…”

Section: Methodsmentioning

confidence: 99%

“…The right C7 dorsal nerve root was then exposed via a C6/C7 hemilaminectomy and partial facetectomy. The nerve root was compressed for 15 minutes (injury, n=10) with a 10gf microvascular clip [15, 16]. Separate rats underwent the same surgical procedures, but did not receive a nerve root compression (sham, n=10) to serve as a surgical control.…”

Section: Methodsmentioning

confidence: 99%

“…A peripheral neuropathic injury, applied via transient compression of the nerve root, induces BSCB permeability, spinal astrocyte activation and pain along different time courses [15, 16, 21]. Compressing the nerve root for just 15 minutes induces a substantial breakdown in the BSCB, which occurs at the same time as the development of mechanical hyperalgesia by day 1 [21].…”

Section: Introductionmentioning

confidence: 99%

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Nerve Root Compression Increases Spinal Astrocytic Vimentin in Parallel With Sustained Pain and Endothelial Vimentin in Association With Spinal Vascular Reestablishment

Smith

Lee

Winkelstein

2017

Spine

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Study Design Temporal immunohistochemistry analysis of spinal cord tissue from a rat model of cervical radiculopathy. Objective The goal was to measure spinal endothelial and astrocytic vimentin expression following a painful nerve root compression to define spinal cellular expression of vimentin in the context of pain. Summary of Background Data The intermediate filament, vimentin, is expressed in a variety of cell types in the spinal cord and is modulated in response to neural pathologies. Early after nerve root compression spinal astrocytes become activated and blood-spinal cord barrier (BSCB) breakdown occurs in parallel with development of pain-related behaviors; these spinal responses remain activated as does the presence of pain. In addition to vimentin, glial fibrillary acidic protein (GFAP) expression is a hallmark of astrocyte activation. In contrast, vascular endothelial cells down-regulate vimentin expression in parallel with vascular breakdown. It is not known whether spinal astrocytes and endothelial cells modulate their expression of vimentin in response to a painful neural injury. Methods Mechanical hyperalgesia was measured and spinal cord tissue was harvested at days 1 and 7 following a unilateral nerve root compression in rats. Vimentin was co-immunolabeled with GFAP to label astrocytes and von Willebrand factor (VWF) for endothelial cells in the spinal cord on the side of injury. Results Spinal astrocytic vimentin increases by day 7 after nerve root compression, corresponding to when mechanical hyperalgesia is maintained. Spinal endothelial vimentin increases as early as day 1 after a painful compression and is even more robust at day 7. Conclusions The delayed elevation in spinal astrocytic vimentin corresponding to sustained mechanical hyperalgesia supports its having a relationship with pain maintenance. Further, since BSCB integrity has been shown to be reestablished by day 7 after a painful compression, endothelial expressed vimentin may help to fortify spinal vasculature contributing to BSCB stability.

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Upregulation of GLT‐1 by treatment with ceftriaxone alleviates radicular pain by reducing spinal astrocyte activation and neuronal hyperexcitability

Nicholson

Gilliland

Winkelstein

2013

J of Neuroscience Research

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Cervical nerve root injury commonly leads to radicular pain. Normal sensation relies on regulation of extracellular glutamate in the spinal cord by glutamate transporters. The goal of this study was to define the temporal response of spinal glutamate transporters (glial glutamate transporter 1 [GLT-1], glutamate-aspartate transporter [GLAST], and excitatory amino acid carrier 1) following nerve root compressions that do or do not produce sensitivity in the rat and to evaluate the role of glutamate uptake in radicular pain by using ceftriaxone to upregulate GLT-1. Compression was applied to the C7 nerve root. Spinal glutamate transporter expression was evaluated at days 1 and 7. In a separate study, rats underwent a painful root compression and were treated with ceftriaxone or the vehicle saline. Glial glutamate transporter expression, astrocytic activation (glial fibrillary acidic protein [GFAP]), and neuronal excitability were assessed at day 7. Both studies measured behavioral sensitivity for 7 days after injury. Spinal GLT-1 significantly decreased (P < 0.04) and spinal GLAST significantly increased (P = 0.036) at day 7 after a root injury that also produced sensitivity to both mechanical and thermal stimuli. Within 1 day after ceftriaxone treatment (day 2), mechanical allodynia began to decrease; both mechanical allodynia and thermal hyperalgesia were attenuated (P < 0.006) by day 7. Ceftriaxone also reduced (P < 0.024) spinal GFAP and GLAST expression, and neuronal hyperexcitability in the spinal dorsal horn, restoring the proportion of spinal neurons classified as wide dynamic range to that of normal. These findings suggest that nerve root-mediated pain is maintained jointly by spinal astrocytic reactivity and neuronal hyperexcitability and that these spinal modifications are associated with reduced glutamate uptake by GLT-1.

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Development of a Duration Threshold for Modulating Evoked Neuronal Responses After Nerve Root Compression Injury

Cited by 7 publications

References 69 publications

Salmon-derived thrombin inhibits development of chronic pain through an endothelial barrier protective mechanism dependent on APC

Salmon-derived thrombin inhibits development of chronic pain through an endothelial barrier protective mechanism dependent on APC

Nerve Root Compression Increases Spinal Astrocytic Vimentin in Parallel With Sustained Pain and Endothelial Vimentin in Association With Spinal Vascular Reestablishment

Upregulation of GLT‐1 by treatment with ceftriaxone alleviates radicular pain by reducing spinal astrocyte activation and neuronal hyperexcitability

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