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.

Level II, prospective observational cohort study.

Nerve root compression induces persistent behavioral hypersensitivity and spinal glial reactivity. Viscoelastic properties of neural tissues suggest that physiologic outcomes may depend on the duration of an applied nerve root compression. This study evaluated the time-dependent properties of the root under compression in the context of pain-related behavioral and physiologic outcomes. The decrease in applied load measured by load relaxation under compression was quantified for rat cervical (C6-C8) roots in situ for durations of 30 sec, 3 min, or 15 min (n ¼ 6). Immediately following compression, the change in the root width relative to its original width was quantified as a measure of its structural recovery. Both load relaxation and structural recovery were significantly ( p < 0.05) correlated with duration of compression. After 30 sec of compression, load relaxed by 22 AE 10%; increasing to 36 AE 18% and 56 AE 20% at 3 and 15 min, respectively. Following 30 sec, 3 min, and 15 min of compression, the root recovered to 91 AE 5%, 88 AE 5 and 72 AE 13% of its original width, respectively. A companion in vivo study imposed these same compression durations and sham procedures to the C7 root to evaluate pain symptoms and spinal glial reactivity. Allodynia was assessed for 7 days to measure behavioral sensitivity. Immunohistochemistry and quantitative densitometry detected GFAP and OX-42 in the dorsal horn at day 7. Significant correlations were detected between compression duration and allodynia ( p < 0.03), and astrocyte and microglial activation ( p < 0.01). These biomechanical and glial results imply that a similar duration of compression may modulate both sustained pain and spinal glial reactivity.

3.