Region‐specific deletions of the glutamate transporter GLT1 differentially affect nerve injury‐induced neuropathic pain in mice

Abstract

Glutamate is a major excitatory neurotransmitter and plays an important role in neuropathic pain, which is frequently caused by nerve damage. According to recent studies, nerve injury induces changes in glutamatergic transmission in the spinal cord and several supraspinal regions, including the periaqueductal gray (PAG). Among glutamate signaling components, accumulating evidence suggests that the glial glutamate transporter GLT1 plays a critical role in neuropathic pain. Indeed, GLT1 expression is reduced in the spinal cord but increased in the PAG after nerve injury, suggesting that the role of GLT1 in neuropathic pain may vary according to the brain region. In this study, we generated PAG-specific and spinal cord-specific GLT1 knockout mice. Nerve injury-induced neuropathic pain was enhanced in spinal cord-specific GLT1 knockout mice but alleviated in PAG-specific GLT1 knockout mice. Thus, nerve injury may enhance glutamatergic neurotransmission from primary sensory neurons to the post-synaptic dorsal horn following downregulation of GLT1 in the spinal cord and result in inadequate descending pain inhibition caused by GLT1 upregulation in the PAG, resulting in neuropathic pain. In addition, ceftriaxone upregulated GLT1 expression in the spinal cord, but not the PAG, of control mice and attenuated tactile hypersensitivity in nerve-injured control mice but not in nerve-injured spinal cord-specific GLT1 knockout mice. Based on these results, the anti-neuropathic pain effect of ceftriaxone is mediated by the upregulation of GLT1 expression in the spinal cord. Thus, selective upregulation of spinal GLT1 and/or downregulation of GLT1 in the PAG represents a potentially novel strategy for the treatment of neuropathic pain.

Satellite Glial Cells: Morphology, functional heterogeneity, and role in pain

“…SGCs take up extracellular glutamate and maintain homeostasis of extracellular glutamate (Fonseca et al, 2005 ; Chiang et al, 2007 , 2008 ). The glutamate transporter, GLT-1, is involved in the transport of glutamate into glial cells (Maeda et al, 2008 ; Zhao et al, 2018 ). Following nerve injury, decreasing of Kir4.1 channel and sequential an increase of extracellular K+ can downregulate GLT-1 (Vit et al, 2008 ), accumulating glutamate, which increases the excitability of the postsynaptic neurons (Sung et al, 2003 ).…”

Burning Mouth Syndrome Cotreated With Zinc and l-Carnosine

“…Pain in BMS is most frequently of neuropathic origin; for instance, BMS has been associated with dopamine pathway dysfunction 1,2 . Furthermore, growing evidence supports that glutamate excitotoxicity in the central nervous system plays an important role in neuropathic pain 9,10 . Zinc and CAR have antiglutamatergic properties that help relieve pain.…”

The Protective Effect of Bergamot Polyphenolic Fraction (BPF) on Chemotherapy-Induced Neuropathic Pain

“…Evidence showed that neuroinflammatory processes are due to impaired glia-neuronal communication. During CIPN, long-term activation of glial cells (astrocytes, microglia, Schwann cells), involvement of cytokine signaling, and changes in glutaminergic transmission have been well documented [36,58,59]. Specifically, chemotherapeutic drugs administration increases the release and production of the glial-derived proinflammatory cytokines responsible for neural cytotoxicity [36].…”