Inhibiting spinal secretory phospholipase A2 after painful nerve root injury attenuates established pain and spinal neuronal hyperexcitability by altering spinal glutamatergic signaling

Neuropathic injury is accompanied by chronic inflammation contributing to the onset and maintenance of pain after an initial insult. In addition to their roles in promoting immune cell activation, inflammatory mediators like secretory phospholipase A2 (sPLA2) modulate nociceptive and excitatory neuronal signaling during the initiation of pain through hydrolytic activity. Despite having a known role in glial activation and cytokine release, it is unknown if sPLA2 contributes to the maintenance of painful neuropathy and spinal hyperexcitability later after neural injury. Using a well-established model of painful nerve root compression, this study investigated if inhibiting spinal sPLA2 7 days after painful injury modulates the behavioral sensitivity and/or spinal dorsal horn excitability that is typically evident. The effects of sPLA2 inhibition on altered spinal glutamatergic signaling was also probed by measuring spinal intracellular glutamate levels and spinal glutamate transporter (GLAST and GLT1) and receptor (mGluR5, GluR1, and NR1) expression. Spinal sPLA2 inhibition at day 7 abolishes behavioral sensitivity, reduces both evoked and spontaneous neuronal firing in the spinal cord, and restores the distribution of neuronal phenotypes to those of control conditions. Inhibiting spinal sPLA2 also increases intracellular glutamate concentrations and restores spinal expression of GLAST, GLT1, mGluR5, and GluR1 to uninjured expression with no effect on NR1. These findings establish a role for spinal sPLA2 in maintaining pain and central sensitization after neural injury and suggest this may be via exacerbating glutamate excitotoxicity in the spinal cord.

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Riluzole effects on behavioral sensitivity and the development of axonal damage and spinal modifications that occur after painful nerve root compression

Journal of Neurosurgery Spine ◽

10.3171/2014.2.spine13672 ◽

2014 ◽

Vol 20 (6) ◽

pp. 751-762 ◽

Cited By ~ 17

Author(s):

Kristen J. Nicholson ◽

Sijia Zhang ◽

Taylor M. Gilliland ◽

Beth A. Winkelstein

Keyword(s):

Spinal Cord ◽

Dorsal Horn ◽

Nerve Root ◽

Mechanical Allodynia ◽

Thermal Hyperalgesia ◽

Neuronal Firing ◽

Nerve Roots ◽

Nerve Root Injury ◽

Root Injury ◽

Behavioral Sensitivity

Object Cervical radiculopathy is often attributed to cervical nerve root injury, which induces extensive degeneration and reduced axonal flow in primary afferents. Riluzole inhibits neuro-excitotoxicity in animal models of neural injury. The authors undertook this study to evaluate the antinociceptive and neuroprotective properties of riluzole in a rat model of painful nerve root compression. Methods A single dose of riluzole (3 mg/kg) was administered intraperitoneally at Day 1 after a painful nerve root injury. Mechanical allodynia and thermal hyperalgesia were evaluated for 7 days after injury. At Day 7, the spinal cord at the C-7 level and the adjacent nerve roots were harvested from a subgroup of rats for immunohistochemical evaluation. Nerve roots were labeled for NF200, CGRP, and IB4 to assess the morphology of myelinated, peptidergic, and nonpeptidergic axons, respectively. Spinal cord sections were labeled for the neuropeptide CGRP and the glutamate transporter GLT-1 to evaluate their expression in the dorsal horn. In a separate group of rats, electrophysiological recordings were made in the dorsal horn. Evoked action potentials were identified by recording extracellular potentials while applying mechanical stimuli to the forepaw. Results Even though riluzole was administered after the onset of behavioral sensitivity at Day 1, its administration resulted in immediate resolution of mechanical allodynia and thermal hyperalgesia (p < 0.045), and these effects were maintained for the study duration. At Day 7, axons labeled for NF200, CGRP, and IB4 in the compressed roots of animals that received riluzole treatment exhibited fewer axonal swellings than those from untreated animals. Riluzole also mitigated changes in the spinal distribution of CGRP and GLT-1 expression that is induced by a painful root compression, returning the spinal expression of both to sham levels. Riluzole also reduced neuronal excitability in the dorsal horn that normally develops by Day 7. The frequency of neuronal firing significantly increased (p < 0.045) after painful root compression, but riluzole treatment maintained neuronal firing at sham levels. Conclusions These findings suggest that early administration of riluzole is sufficient to mitigate nerve root–mediated pain by preventing development of neuronal dysfunction in the nerve root and the spinal cord.

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Mechanical Thresholds for Initiation and Persistence of Pain Following Nerve Root Injury: Mechanical and Chemical Contributions at Injury

Journal of Biomechanical Engineering ◽

10.1115/1.1695571 ◽

2004 ◽

Vol 126 (2) ◽

pp. 258-263 ◽

Cited By ~ 24

Author(s):

Beth A. Winkelstein ◽

Joyce A. DeLeo

Keyword(s):

Nerve Root ◽

Computational Models ◽

Mechanical Deformation ◽

Lumbar Radiculopathy ◽

Nerve Roots ◽

Injury Biomechanics ◽

Nerve Root Injury ◽

Sham Exposure ◽

Behavioral Sensitivity ◽

Mechanical Thresholds

There is much evidence supporting the hypothesis that magnitude of nerve root mechanical injury affects the nature of the physiological responses which can contribute to pain in lumbar radiculopathy. Specifically, injury magnitude has been shown to modulate behavioral hypersensitivity responses in animal models of radiculopathy. However, no study has determined the mechanical deformation thresholds for initiation and maintenance of the behavioral sensitivity in these models. Therefore, it was the purpose of this study to quantify the effects of mechanical and chemical contributions at injury on behavioral outcomes and to determine mechanical thresholds for pain onset and persistence. Male Holtzman rats received either a silk or chromic gut ligation of the L5 nerve roots, a sham exposure of the nerve roots, or a chromic exposure in which no mechanical deformation was applied but chromic gut material was placed on the roots. Using image analysis, nerve root radial strains were estimated at the time of injury. Behavioral hypersensitivity was assessed by measuring mechanical allodynia continuously throughout the study. Chromic gut ligations produced allodynia responses for nerve root strains at two-thirds of the magnitudes of those strains which produced the corresponding behaviors for silk ligation. Thresholds for nerve root compression producing the onset (8.4%) and persistence of pain (17.4%–22.2%) were determined for silk ligation in this lumbar radiculopathy model. Such mechanical thresholds for behavioral sensitivity in a painful radiculopathy model begin to provide biomechanical data which may have utility in broader experimental and computational models for relating injury biomechanics and physiologic responses of pain.

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Biomechanics and Painful Injuries: Tissue and CNS Responses for Nerve Root Mechanical Injuries

Advances in Bioengineering ◽

10.1115/imece2003-43117 ◽

2003 ◽

Author(s):

Beth A. Winkelstein ◽

Raymond D. Hubbard ◽

Joyce A. DeLeo

Keyword(s):

Nerve Root ◽

Animal Studies ◽

Nerve Roots ◽

Edema Formation ◽

Injury Biomechanics ◽

Pain Behaviors ◽

Nerve Root Injury ◽

Nociceptive Responses ◽

Behavioral Sensitivity ◽

Mechanical Insult

Pain affects as many as 50 million Americans, with annual costs estimated as high as $90 billion. Unfortunately, the mechanism of injuries leading to persistent pain syndromes remain largely uncharacterized. A common painful injury results due from mechanical loading of nerve roots, which can occur for spinal injuries in both the low back and neck. Relationships have been demonstrated between tissue compression and behavioral hypersensitivity responses in animal models, with differential patterns of sensitivity depending on the nature of the mechanical insult (Colburn et al., 1999). Mechanical allodynia (MA) is an increased behavioral sensitivity to a non-noxious stimulus and is observed in the dermatome of the injured tissue. It can be measured by the frequency of paw withdrawals elicited by stimulation with normally non-noxious von Frey filaments. Allodynia is a clinical measure of sensitivity and, therefore, provides a useful gauge of nociceptive responses. Animal studies have shown that compression of neural structures initiates a variety of physiologic responses, including decreased electrical activity, increased edema formation, and increased endoneurial pressure in the region of compression (Lundborg et al., 1983; Olmarker et al., 1989, 1990; Pedowitz et al., 1992). While these studies document physiologic changes immediately following injury, they do not describe the temporal nature of these changes following tissue loading as they relate to pain behaviors. Moreover, despite this evidence of edema formation and increased endoneurial pressure locally in the nerve roots, no study has simultaneously documented local changes in nerve root geometry following compressive injury and how these changes may be linked to the onset and/or maintenance of pain-associated behaviors. Therefore, this study examines injury biomechanics for pain-behaviors in a radiculopathy (nerve root injury) model and temporally characterizes the local geometric changes in the nerve root for a series of postsurgical time points following compressive injury. While these results indicate that compression magnitude clearly modulates pain responses, the local nerve root swelling does not appear to directly drive behavioral changes. This suggests a complicated physiology for injury which likely contributes to the manifestation of pain. Findings are also presented for preliminary investigations into tissue rebound/recovery responses for varied mechanical insult magnitudes to begin to understand potential injury mechanisms leading to pain.

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Utility of modified transarticular screw in the middle and lower cervical spine as intermediate fixation in posterior long fusion surgery

Journal of Neurosurgery Spine ◽

10.3171/2009.5.spine08348 ◽

2009 ◽

Vol 11 (5) ◽

pp. 555-561 ◽

Cited By ~ 11

Author(s):

Hiroshi Miyamoto ◽

Masatoshi Sumi ◽

Koki Uno

Keyword(s):

Spinal Cord ◽

Cervical Spine ◽

Cobb Angle ◽

Nerve Root ◽

Japanese Orthopaedic Association ◽

Transarticular Screw ◽

Fusion Surgery ◽

Nerve Root Injury ◽

A New Technique

Object The use of a pedicle screw (PS) in the cervical spine ensures strong fixation. However, 6.7–29% of such screws appear to be malpositioned using manual insertion techniques, especially at C-3 to C-6 where the pedicle diameter is smaller, potentially causing catastrophic complications such as vertebral artery (VA) and spinal cord or nerve root injuries. To optimize safety, the authors use a new technique: cephalad and/or caudad ends at C-2 and C-7/T-1, respectively, are fixed with PSs, and intermediate points around C3–6 are fixed using a modified transarticular screw technique that captures 3 dorsal cortices and preserves the ventral cortex of the facet in posterior long fusion surgery involving occipitospinal fixation. The purpose of the present study was to demonstrate this technique and evaluate the clinical and radiological outcomes. Methods Thirty-nine patients, 8 men and 31 women, with a mean age of 61.7 ± 11.0 years at surgery, were included in the study. Twenty-eight occipitospinal fusions and 11 posterior long fusions were performed. Patients were divided into 2 groups: a rheumatoid arthritis (RA) group consisting of 26 patients and a non-RA group of 13 patients including 7 with athetoid cerebral palsy. Clinical outcomes were evaluated according to the Japanese Orthopaedic Association (JOA) score. For radiological evaluation, the Cobb angle on lateral radiographs was measured preoperatively, postoperatively, and at the final follow-up, and the degree of realignment from pre- to postoperation and the loss of correction from postoperation to the follow-up were compared between the 2 patient groups. Results The recovery rate of the JOA score was 50.6 ± 20.7% in the RA group and 37.3 ± 24.3% in the non-RA group. Neither VA injury nor spinal cord or nerve root injury occurred among this series. The degree of realignment was greater in the non-RA group (9.2 ± 13.9°) than the RA group (1.4 ± 12.7°) as the Cobb angle was more kyphotic preoperatively in the non-RA group (2.9 ± 18.6°) than in the RA group (17.4 ± 15.7°). However, 38.5% of patients in the non-RA group had a correction loss > 10% compared with 7.7% in the RA group; this difference was statistically significant. Conclusions The featured transarticular screw technique, which preserves the ventral cortex of the facet, as intermediate fixation in long fusion is a safe and easy procedure with few complications. It ensures acceptable clinical and radiological outcomes, especially in patients with RA.

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Inflammation after spinal cord injury: a review of the critical timeline of signaling cues and cellular infiltration

Journal of Neuroinflammation ◽

10.1186/s12974-021-02337-2 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Daniel J. Hellenbrand ◽

Charles M. Quinn ◽

Zachariah J. Piper ◽

Carolyn N. Morehouse ◽

Jordyn A. Fixel ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Immune Cell ◽

Sensory Function ◽

Glutamate Excitotoxicity ◽

Secondary Injury ◽

Extensive Literature ◽

Secondary Damage ◽

Cord Injury

AbstractTraumatic spinal cord injury (SCI) is a devastating neurological condition that results in a loss of motor and sensory function. Although extensive research to develop treatments for SCI has been performed, to date, none of these treatments have produced a meaningful amount of functional recovery after injury. The primary injury is caused by the initial trauma to the spinal cord and results in ischemia, oxidative damage, edema, and glutamate excitotoxicity. This process initiates a secondary injury cascade, which starts just a few hours post-injury and may continue for more than 6 months, leading to additional cell death and spinal cord damage. Inflammation after SCI is complex and driven by a diverse set of cells and signaling molecules. In this review, we utilize an extensive literature survey to develop the timeline of local immune cell and cytokine behavior after SCI in rodent models. We discuss the precise functional roles of several key cytokines and their effects on a variety of cell types involved in the secondary injury cascade. Furthermore, variations in the inflammatory response between rats and mice are highlighted. Since current SCI treatment options do not successfully initiate functional recovery or axonal regeneration, identifying the specific mechanisms attributed to secondary injury is critical. With a more thorough understanding of the complex SCI pathophysiology, effective therapeutic targets with realistic timelines for intervention may be established to successfully attenuate secondary damage.

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Complement receptor 2 is up regulated in the spinal cord following nerve root injury and modulates the spinal cord response

Journal of Neuroinflammation ◽

10.1186/s12974-015-0413-6 ◽

2015 ◽

Vol 12 (1) ◽

Cited By ~ 5

Author(s):

Rickard P. F. Lindblom ◽

Alexander Berg ◽

Mikael Ström ◽

Shahin Aeinehband ◽

Cecilia A. Dominguez ◽

...

Keyword(s):

Spinal Cord ◽

Nerve Root ◽

Complement Receptor ◽

Nerve Root Injury ◽

Complement Receptor 2 ◽

Root Injury

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Non-MHC gene regulation of nerve root injury induced spinal cord inflammation and neuron death

Journal of Neuroimmunology ◽

10.1016/s0165-5728(99)00136-8 ◽

1999 ◽

Vol 101 (1) ◽

pp. 87-97 ◽

Cited By ~ 29

Author(s):

Fredrik Piehl ◽

Cecilia Lundberg ◽

Mohsen Khademi ◽

Anders Bucht ◽

Ingrid Dahlman ◽

...

Keyword(s):

Spinal Cord ◽

Gene Regulation ◽

Nerve Root ◽

Neuron Death ◽

Nerve Root Injury ◽

Root Injury

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Rating Spinal Nerve Extremity Impairment Using the Sixth Edition

Guides Newsletter ◽

10.1001/amaguidesnewsletters.2009.julaug01 ◽

2009 ◽

Vol 14 (4) ◽

pp. 1-6

Author(s):

Christopher R. Brigham

Keyword(s):

Nerve Root ◽

Spinal Nerve ◽

Upper Extremities ◽

Motor Deficits ◽

Nerve Injuries ◽

Sixth Edition ◽

Federal Employee ◽

Nerve Root Injury ◽

Root Injury ◽

Rating Process

Abstract The AMAGuides to the Evaluation of Permanent Impairment (AMA Guides), Sixth Edition, does not provide a separate mechanism for rating spinal nerve injuries as extremity impairment; radiculopathy was reflected in the spinal rating process in Chapter 17, The Spine and Pelvis. Certain jurisdictions, such as the Federal Employee Compensation Act (FECA), rate nerve root injury as impairment involving the extremities rather than as part of the spine. This article presents an approach to rate spinal nerve impairments consistent with the AMA Guides, Sixth Edition, methodology. This approach should be used only when a jurisdiction requires ratings for extremities and precludes rating for the spine. A table in this article compares sensory and motor deficits according to the AMA Guides, Sixth and Fifth Editions; evaluators should be aware of changes between editions in methodology used to assign the final impairment. The authors present two tables regarding spinal nerve impairment: one for the upper extremities and one for the lower extremities. Both tables were developed using the methodology defined in the sixth edition. Using these tables and the process defined in the AMA Guides, Sixth Edition, evaluators can rate spinal nerve impairments for jurisdictions that do not permit rating for the spine and require rating for radiculopathy as an extremity impairment.

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