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

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

Molecular Pain ◽

10.1177/17448069211066221 ◽

2021 ◽

Vol 17 ◽

pp. 174480692110662

Author(s):

Sonia Kartha ◽

Prabesh Ghimire ◽

Beth A Winkelstein

Keyword(s):

Spinal Cord ◽

Nerve Root ◽

Immune Cell ◽

Neuronal Firing ◽

Glutamate Excitotoxicity ◽

Neural Injury ◽

Secretory Phospholipase ◽

Nerve Root Injury ◽

Glutamatergic Signaling ◽

Behavioral Sensitivity

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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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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Anatomy of the L5 nerve root in the pelvis for safe sacral screw placement: a cadaveric study

Journal of Neurosurgery Spine ◽

10.3171/2021.8.spine21962 ◽

2021 ◽

pp. 1-6

Author(s):

Shota Tamagawa ◽

Takatoshi Okuda ◽

Hidetoshi Nojiri ◽

Tatsuya Sato ◽

Rei Momomura ◽

...

Keyword(s):

Nerve Root ◽

Sagittal Plane ◽

Pedicle Screws ◽

Cadaveric Study ◽

Nerve Roots ◽

Nerve Root Injury ◽

Inflection Points ◽

Root Injury ◽

The Right ◽

Intervertebral Foramina

OBJECTIVE Previous reports have focused on the complications of L5 nerve root injury caused by anterolateral misplacement of the S1 pedicle screws. Anatomical knowledge of the L5 nerve root in the pelvis is essential for safe and effective placement of the sacral screw. This cadaveric study aimed to investigate the course of the L5 nerve root in the pelvis and to clarify a safe zone for inserting the sacral screw. METHODS Fifty-four L5 nerve roots located bilaterally in 27 formalin-fixed cadavers were studied. The ventral rami of the L5 nerve roots were dissected along their courses from the intervertebral foramina to the lesser pelvis. The running angles of the L5 nerve roots from the centerline were measured in the coronal plane. In addition, the distances from the ala of the sacrum to the L5 nerve roots were measured in the sagittal plane. RESULTS The authors found that the running angles of the L5 nerve roots changed at the most anterior surface of the ala of the sacrum. The angles of the bilateral L5 nerve roots from the right and left L5 intervertebral foramina to their inflection points were 13.77° ± 5.01° and 14.65° ± 4.71°, respectively. The angles of the bilateral L5 nerve roots from the right and left inflection points to the lesser pelvis were 19.66° ± 6.40° and 20.58° ± 5.78°, respectively. There were no significant differences between the angles measured in the right and left nerve roots. The majority of the L5 nerves coursed outward after changing their angles at the inflection point. The distances from the ala of the sacrum to the L5 nerve roots in the sagittal plane were less than 1 mm in all cases, which indicated that the L5 nerve roots were positioned close to the ala of the sacrum and had poor mobility. CONCLUSIONS All of the L5 nerve roots coursed outward after exiting the intervertebral foramina and never inward. To prevent iatrogenic L5 nerve root injury, surgeons should insert the S1 pedicle screw medially with an angle > 0° toward the inside of the S1 anterior foramina and the sacral alar screw laterally with an angle > 30°.

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Cyclooxygenase-2 inhibitor SC-236 attenuates mechanical allodynia following nerve root injury in rats

Journal of Orthopaedic Research® ◽

10.1002/jor.1100180618 ◽

2000 ◽

Vol 18 (6) ◽

pp. 977-982 ◽

Cited By ~ 17

Author(s):

Joyce A. DeLeo ◽

Hiroshi Hashizume ◽

Maria D. Rutkowski ◽

James N. Weinstein

Keyword(s):

Nerve Root ◽

Mechanical Allodynia ◽

Cyclooxygenase 2 ◽

Nerve Root Injury ◽

Root Injury

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Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 15: Electrophysiological monitoring and lumbar fusion

Journal of Neurosurgery Spine ◽

10.3171/2014.4.spine14324 ◽

2014 ◽

Vol 21 (1) ◽

pp. 102-105 ◽

Cited By ~ 15

Author(s):

Alok Sharan ◽

Michael W. Groff ◽

Andrew T. Dailey ◽

Zoher Ghogawala ◽

Daniel K. Resnick ◽

...

Keyword(s):

Nerve Root ◽

Lumbar Fusion ◽

Pedicle Screws ◽

Limited Evidence ◽

Direct Stimulation ◽

Nerve Roots ◽

Fusion Surgery ◽

Nerve Root Injury ◽

Root Injury ◽

Stimulation Of

Intraoperative monitoring (IOM) is commonly used during lumbar fusion surgery for the prevention of nerve root injury. Justification for its use stems from the belief that IOM can prevent nerve root injury during the placement of pedicle screws. A thorough literature review was conducted to determine if the use of IOM could prevent nerve root injury during the placement of instrumentation in lumbar or lumbosacral fusion. There is no evidence to date that IOM can prevent injury to the nerve roots. There is limited evidence that a threshold below 5 mA from direct stimulation of the screw can indicate a medial pedicle breach by the screw. Unfortunately, once a nerve root injury has taken place, changing the direction of the screw does not alter the outcome. The recommendations formulated in the original guideline effort are neither supported nor refuted with the evidence obtained with the current studies.

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A novel anatomo-physiologic high-grade spondylolisthesis model to evaluate L5 nerve stretch injury after spondylolisthesis reduction

Neurosurgical Review ◽

10.1007/s10143-021-01721-z ◽

2021 ◽

Author(s):

Basem Ishak ◽

Clifford A. Pierre ◽

Darius Ansari ◽

Stefan Lachkar ◽

Alexander von Glinski ◽

...

Keyword(s):

Nerve Root ◽

Nerve Palsy ◽

Mechanical Strain ◽

Pedicle Screws ◽

High Grade ◽

Nerve Roots ◽

Nerve Root Injury ◽

Root Injury ◽

Fresh Frozen ◽

Measurable Change

AbstractL5 nerve palsy is a well-known complication following reduction of high-grade spondylolisthesis. While several mechanisms for its occurrence have been proposed, the hypothesis of L5 nerve root strain or displacement secondary to mechanical reduction remains poorly studied. The aim of this cadaveric study is to determine changes in morphologic parameters of the L5 nerve root during simulated intraoperative reduction of high-grade spondylolisthesis. A standard posterior approach to the lumbosacral junction was performed in eight fresh-frozen cadavers with lumbosacral or lumbopelvic screw fixation. Wide decompressions of the spinal canal and L5 nerve roots with complete facetectomies were accomplished with full exposure of the L5 nerve roots. A 100% translational slip was provoked by release of the iliolumbar ligaments and cutting the disc with the attached anterior longitudinal ligament. To evaluate the path of the L5 nerves during reduction maneuvers, metal bars were inserted bilaterally at the inferomedial aspects of the L5 pedicle at a distance of 10 mm from the midpoint of the L5 pedicle screws. There was no measurable change in length of the L5 nerve roots after 50% and 100% reduction of spondylolisthesis. Mechanical strain or displacement during reduction is an unlikely cause of L5 nerve root injury. Further anatomical or physiological studies are necessary to explore alternative mechanisms of L5 nerve palsy in the setting of high-grade spondylolisthesis correction, and surgeons should favor extensive surgical decompression of the L5 nerve roots when feasible.

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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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PATHOANATOMIC BASIS FOR STRETCH-INDUCED LUMBAR NERVE ROOT INJURY WITH A REVIEW OF THE LITERATURE

Neurosurgery ◽

10.1227/01.neu.0000347002.67982.8f ◽

2009 ◽

Vol 65 (1) ◽

pp. 161-168 ◽

Cited By ~ 15

Author(s):

Sameer A. Kitab ◽

Vincent J. Miele ◽

William F. Lavelle ◽

Edward C. Benzel

Keyword(s):

Spinal Deformity ◽

Nerve Root ◽

Nerve Roots ◽

Nerve Root Injury ◽

Functional Spinal Unit ◽

Root Injury ◽

Lumbar Nerve Root ◽

The Face ◽

Anterior Posterior

Abstract OBJECTIVE Persistent pain originating from a dysfunctional lumbar motion segment poses significant challenges in the clinical arena. Although the predominance of the existing spine literature has addressed nerve root compression as the principal cause of pain, it is equally likely that a stretch mechanism may be responsible for all or part of the pathology. METHODS The literature supporting the role of stretch damage as a primary cause of nerve root injury and pain was systematically reviewed. Pathoanatomic considerations between nerve roots and juxtaposed environment are described and correlated with the available literature. Potential anatomic relationships that may lead to stretch-induced injury are delineated. RESULTS A dynamic lumbar functional spinal unit that encloses a tethered nerve root can create significant stretch and/or compression. This phenomenon may be present in a variety of pathological conditions. These include anterior, posterior, and rotatory olisthesis as well as degenerative conditions such as the loss of disc interspace height and frank multisegment spinal deformity. Although numerous studies have demonstrated that stretch can result in nerve damage, the pathophysiology that may associate nerve stretch with chronic pain has yet to be determined. CONCLUSION The current literature concerning stretch-related injury to nerve roots is reviewed, and a conceptual framework for its diagnosis and treatment is proposed and graphically illustrated using cadaveric specimens. The dynamic biomechanical and functional interrelationships between neural structures and adjacent connective tissue elements are particularly important in the face of spinal deformity.

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