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Dissertation
Positive allosteric modulation of glutamate transporter GLT-1 (EAAT2) provides antinociception in rodent models of neuropathic pain
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2025
DOI:
https://doi.org/10.17918/00011129
Abstract
Neuropathic pain, a complex and debilitating condition of the somatosensory nervous system, presents significant clinical challenges due to the limited efficacy and adverse effects of current treatments. A promising target for pain modulation is astrocytic glutamate transporter GLT-1 (EAAT2), which plays a key role in maintaining extracellular glutamate homeostasis. This study investigates the antinociceptive efficacy and mechanism of a novel positive allosteric modulator (PAM) of GLT-1, NA-014, in a mouse model of neuropathic pain. To induce neuropathic pain behaviors, adult male and female C57BL/6J mice underwent spared nerve injury. Both evoked and spontaneous pain were assessed using behavioral assays, including von Frey, acetone evaporation, conditioned place preference, and mechanical conflict avoidance. To determine the site of action, region-specific siRNA knockdown of GLT-1 was performed in the spinal cord and anterior cingulate cortex (ACC). Off-target effects on locomotion, anxiety-like behavior, and spatial memory were evaluated through open field, Y-maze, and elevated plus maze tests. NA-014 produced a dose-dependent reduction in mechanical allodynia and cold hypersensitivity in both sexes, achieving efficacy comparable to gabapentin, with no evidence of locomotor or memory effects at minimally effective doses. Both systemic and intrathecal administration of NA-014 resulted in robust antinociception, whereas direct ACC administration was ineffective. Knockdown of GLT-1 in the spinal cord, but not in the ACC, abolished the antinociceptive effects of NA-014, demonstrating a spinal mechanism of action. NA-014 did not decrease affective pain behaviors in the mechanical conflict avoidance assay, and there was no evidence of toxicity or changes in GLT-1 expression following a twice daily, 7 day treatment. These findings demonstrate that positive allosteric modulation of spinal GLT-1 by NA-014 produces effective, non-sedating antinociception in a mouse model of neuropathic pain. The results highlight spinal GLT-1 as a key mediator of pain relief and support the further development of GLT-1 PAMs as a novel, non-opioid therapeutic strategy for neuropathic pain management.
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Details
- Title
- Positive allosteric modulation of glutamate transporter GLT-1 (EAAT2) provides antinociception in rodent models of neuropathic pain
- Creators
- Rhea Temmermand
- Contributors
- Andreia Mortensen (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 191 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991022076428404721