Upregulation of GLT‐1 by treatment with ceftriaxone alleviates radicular pain by reducing spinal astrocyte activation and neuronal hyperexcitability

Abstract

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.

Whole-body Vibration at Thoracic Resonance Induces Sustained Pain and Widespread Cervical Neuroinflammation in the Rat

“…Accordingly, we defined the resonance frequency of the rat spine, because that species is used to study pain and evaluate potential therapeutics [23,39,60,78,85,86]. We hypothesized that vibration at resonance produces more robust pain than nonresonant WBV [11,40] and that the neuroimmune cellular and molecular pathways are more extensively activated for that WBV exposure.…”

“…7). Neuroinflammation is associated with pain [22,75,79], and spinal glial activation occurs after a variety of painful injuries [18,22,25,31,32,38,60,79,82,87,88,90]. The proinflammatory cytokines, IL-6 and tumor necrosis factor-a, nearly double after acceleration that was painful and occurred at the resonance of 8 Hz, like painful nerve injury [67,88,89].…”

“…Of note, PKCe is also the only peripheral mediator that was probed. There is strong evidence across a variety of pain models of different tissue injuries that spinal neuroimmune responses are correlated with pain [2,27,29,60,61,65,67,81,[87][88][89]. Importantly, similar pain pathways are initiated by WBV, suggesting potential therapeutic targets and/or helping to identify treatments for patients with these symptoms.…”

Activity-triggered tetrapartite neuron–glial interactions following peripheral injury

“…Peripheral nerve injury down-regulates GLT-1 in the spinal cord dorsal horn [55], which may lead to accumulation of glutamate in the synaptic cleft. Restoring GLT-1 with ceftriaxone relieved hyperalgesia [56]. The down-regulation of GLT-1 results in an enhanced extrasynaptic NMDA receptor activation, likely involving glutamate spillover to the extrasynaptic site [57].…”

Neuroprotective Effects of the Glutamate Transporter Activator (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) following Traumatic Brain Injury in the Adult Rat

“…[18][19][20] Developing EAAT2 as a target for neuroprotection has been explored through the discovery of compounds that can either increase EAAT2 expression or increase the activity of the transporter. 21,22 The b-lactam antibiotic ceftriaxone increases EAAT2 expression and has been shown to decrease neuronal damage in animal models of chronic neurodegenerative disorders, 23-25 reduce brain glutamate levels, edema, and neuronal death after TBI in the rat, [26][27][28][29] and attenuate neuropathic pain 30,31 and cytokine production after spinal cord injury in the rat. 32 Compounds such as riluzole, [33][34][35][36][37] guanosine, 38,39 nicergoline, 40 (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), and Parawixin1, 43,44 have been reported to be neuroprotective in several models of CNS injury by increasing EAAT2 activity.…”