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

Abstract

<jats:sec> <jats:title>Object</jats:title> <jats:p>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.</jats:p></jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p></jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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 &lt; 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 &lt; 0.045) after painful root compression, but riluzole treatment maintained neuronal firing at sham levels.</jats:p></jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p></jats:sec>

Burst and Tonic Spinal Cord Stimulation Differentially Activate GABAergic Mechanisms to Attenuate Pain in a Rat Model of Cervical Radiculopathy

“…Compression of the right C7 dorsal nerve root was performed using procedures described previously [19], [20]. Briefly, rats were anesthetized with inhaled isoflurane (4% for induction, 2-3% for maintenance), and placed in a prone position.…”

Superoxide Dismutase‐Loaded Porous Polymersomes as Highly Efficient Antioxidants for Treating Neuropathic Pain

“…[9] Several animal models of nerve root compression have shown that even a transient, 15-minute compression applied to the nerve root is sufficient to induce sustained pain. [10, 11] In addition to pain, axonal damage and myelin degeneration are evident in the nerve root by 7 days after compression. [11] Such damage is hypothesized to relate to and cause neuronal dysfunction and contribute to the maintenance of pain by impaired axonal transport in the nerve root and disrupting the afferent signals that communicate to synapses in the spinal cord dorsal horn.…”

“…[40] In this study, administration of the SOD-loaded porous polymersomes partially prevented the axonal damage and disorganization (Figure 3c) that usually occurs after painful nerve root compression. [11] Treatment with the empty polymersomes exhibited the most disruption in NF200 labeling and axonal thinning, while treatment with both free SOD regiments displayed axonal damage to a lesser extent, suggesting that free SOD antioxidant treatment administration may delay the onset of pain, but alone may not sufficiently reduce ROS to rescue neuronal health after injury. The prevention of axonal damage with SOD-loaded porous polymersomes also suggests that these polymersomes may have greater antioxidant activity than free antioxidant alone, especially since it is known that free antioxidants are rapidly degraded in-vivo.…”

Pain from intra-articular NGF or joint injury in the rat requires contributions from peptidergic joint afferents

“…Thermal hypersensitivity was measured following mechanical assessment using a commercially available device (UC San Diego) and customary methods [25]. After acclimation to the apparatus for 30 minutes, the withdrawal latency for each rat was averaged across forepaws over three testing rounds on each day; baseline measurements were averaged over two days before injections.…”