Antinociceptive Effect of Riluzole in Rats with Neuropathic Spinal Cord Injury Pain

Hama, Aldric; Sagen, Jacqueline

doi:10.1089/neu.2010.1539

Cited by 49 publications

(64 citation statements)

References 44 publications

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“…3). Inhibiting neuronal signaling in the brain may be essential to riluzole's antinociceptive properties 26 and may augment its effects to produce the pronounced reduction in behavioral sensitivity and neuronal signaling despite the presence of axonal swelling and discontinuities in neurofilament labeling (Figs. 1, 2, and 5).…”

Section: Discussionmentioning

confidence: 99%

“…Riluzole has been shown previously to cross the blood-brain barrier rapidly and to reduce spinal glutamate and mechanical hyperalgesia within 1 hour after an intraperitoneal injection. 15,26,76 After spinal cord contusion, riluzole alleviates pain when it is systemically administered or by an intracerebroventricular injection; yet, it is ineffective in alleviating behavioral sensitivity when it is directly administered into the intrathecal space of the spinal cord. 26 Therefore, the effects of riluzole on supraspinal glutamate appear to play a critical role in reducing pain associated with spinal cord injury.…”

Section: Discussionmentioning

confidence: 99%

“…15,26,76 After spinal cord contusion, riluzole alleviates pain when it is systemically administered or by an intracerebroventricular injection; yet, it is ineffective in alleviating behavioral sensitivity when it is directly administered into the intrathecal space of the spinal cord. 26 Therefore, the effects of riluzole on supraspinal glutamate appear to play a critical role in reducing pain associated with spinal cord injury. Since supraspinal signaling after radicular pain has not been well defined, it is unclear whether such effects also contribute to the reduced behavioral sensitivity that was observed in this study (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…It is also unclear whether a single dose of riluzole is sufficient to provide sustained pain relief when administered after pain has developed. 26 This study investigates whether a single dose of riluzole can eliminate behavioral sensitivity and axonal damage in the injured root as well as prevent the spinal changes that develop after root compression in a rat pain model. We hypothesized that riluzole would abolish behavioral sensitivity by preserving axonal morphology and would abate spinal modifications of CGRP and neuronal excitability that are observed after painful root compression.…”

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confidence: 99%

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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

Nicholson

Zhang

Gilliland

et al. 2014

SPI

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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

Nicholson

Zhang

Gilliland

et al. 2014

SPI

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“…Down regulation of GLT-1 occurs in activated astrocytes; seen often following chronic opioid therapy and in chronic pain models. Efficacy has been demonstrated after intraspinal ceftriaxone in 1) hyperalgesia and allodynia following chronic morphine [8], 2) pain following peripheral neuropathy, inflammation or spinal cord injury [20,21,34] 3) tactile hyperalgesia and progression of motor weakness and paralysis in animal models of multiple sclerosis [8]. There are also ongoing studies regarding the efficacy of GLT-1 up-regulation in other conditions mediated by enhanced extracellular glutamate such as Alzheimer's disease, Huntington's disease, epilepsy, amyotrophic lateral sclerosis and the regulation of addictive behaviors [35][36][37][38][39].…”

Section: Translational Potential Of Glt-1 Up-regulation In the Treatmmentioning

confidence: 99%

Glutamate Transporter Activators as Anti-Nociceptive Agents

Stephens¹

2011

EAJM

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The effective management of chronic pain remains enigmatic. There is a paucity of effective mechanistically-based approaches employed. Chronic visceral pain is a particularly difficult subcategory to manage. Glutamate is the most predominant excitatory neurotransmitter and mediates many aspects of sensory function including acute and chronic pain. There is a growing literature describing the efficacy of physiologically dominant glutamate transporter GLT-1 up-regulation in attenuating chronic visceral and somatic nociception. Since glutamate is the major excitatory neurotransmitter released in the first central synapse of the pain-transmitting afferent neurons, augmentation of GLT-1 activity, which reduces extracellular levels of glutamate, may be an important target for pain management strategies. This review summarizes studies in our laboratory and others which highlight findings that GLT-1 up-regulation by transgenic, pharmacologic and viral transfection approaches attenuate a host of nociceptive responses emanating from visceral or somatic sources in animal models. The study also outlines the future work that will be required to ascertain the translational potential of this approach.

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Glutamate Transport System as a Novel Therapeutic Target in Chronic Pain: Molecular Mechanisms and Pharmacology

Gegelashvili

Bjerrum

2017

Advances in Neurobiology

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The vast majority of peripheral neurons sensing noxious stimuli and conducting pain signals to the dorsal horn of the spinal cord utilize glutamate as a chemical transmitter of excitation. High-affinity glutamate transporter subtypes GLAST/EAAT1, GLT1/EAAT2, EAAC1/EAAT3, and EAAT4, differentially expressed on sensory neurons, postsynaptic spinal interneurons, and neighboring glia, ensure fine modulation of glutamate neurotransmission in the spinal cord. The glutamate transport system seems to play important roles in molecular mechanisms underlying chronic pain and analgesia. Downregulation of glutamate transporters (GluTs) often precedes or occurs simultaneously with development of hypersensitivity to thermal or tactile stimuli in various models of chronic pain. Moreover, antisense knockdown or pharmacological inhibition of these membrane proteins can induce or aggravate pain. In contrast, upregulation of GluTs by positive pharmacological modulators or by viral gene transfer to the spinal cord can reverse the development of such pathological hypersensitivity. Furthermore, some multi-target drugs displaying analgesic properties (e.g., tricyclic antidepressant amitriptyline, riluzole, anticonvulsant valproate, tetracycline antibiotic minocycline, β-lactam antibiotic ceftriaxone and its structural analog devoid of antibacterial activity, clavulanic acid) can significantly increase the spinal glutamate uptake. Thus, mounting evidence points at GluTs as prospective therapeutic target for chronic pain treatment. However, design and development of new analgesics based on the modulation of glutamate uptake will require more precise knowledge of molecular mechanisms underlying physiological or aberrant functioning of this transport system in the spinal cord.

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Antinociceptive Effect of Riluzole in Rats with Neuropathic Spinal Cord Injury Pain

Cited by 49 publications

References 44 publications

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

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

Glutamate Transporter Activators as Anti-Nociceptive Agents

Glutamate Transport System as a Novel Therapeutic Target in Chronic Pain: Molecular Mechanisms and Pharmacology

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