Chronic at-level thermal hyperalgesia following rat cervical contusion spinal cord injury is accompanied by neuronal and astrocyte activation and loss of the astrocyte glutamate transporter, GLT1, in superficial dorsal horn

Abstract

Neuropathic pain is a form of pathological nociception that occurs in a significant portion of traumatic spinal cord injury (SCI) patients, resulting in debilitating and often long-term physical and psychological burdens. While many peripheral and central mechanisms have been implicated in neuropathic pain, central sensitization of dorsal horn spinothalamic tract (STT) neurons is a major underlying substrate. Furthermore, dysregulation of extracellular glutamate homeostasis and chronic astrocyte activation play important underlying roles in persistent hyperexcitability of these superficial dorsal horn neurons. To date, central sensitization and astrocyte changes have not been characterized in cervical SCI-induced neuropathic pain models, despite the fact that a major portion of SCI patients suffer contusion trauma to cervical spinal cord. In this study, we have characterized two rat models of unilateral cervical contusion SCI that behaviorally result in chronic persistence of thermal hyperalgesia in the ipsilateral forepaw. In addition, we find that STT neurons are chronically activated in both models when compared to laminectomy-only uninjured rats. Finally, persistent astrocyte activation and significantly reduced expression of the major CNS glutamate transporter, GLT1, in superficial dorsal horn astrocytes are associated with both excitability changes in STT neurons and the neuropathic pain behavioral phenotype. In conclusion, we have characterized clinically-relevant rodent models of cervical contusion-induced neuropathic pain that result in chronic activation of both STT neurons and astrocytes, as well as compromise in astrocyte glutamate transporter expression. These models can be used as important tools to further study mechanisms underlying neuropathic pain post-SCI and to test potential therapeutic interventions.

Human iPS cell-derived astrocyte transplants preserve respiratory function after spinal cord injury

“…We have consistently observed significant GLT1 downregulation in endogenous reactive astrocyte populations in both contusion and crush, as well as both cervical and thoracic, models of SCI (Lepore et al, 2011a; Lepore et al, 2011c; Li et al, 2014b; Putatunda et al, 2014; Watson et al, 2014). When we selectively increased GLT1 expression in these endogenous astrocytes in the unilateral cervical contusion model using an AAV8 vector, we paradoxically found that secondary degeneration of PhMNs and diaphragm denervation were worsened (Li et al, 2014b).…”

GLT1 overexpression reverses established neuropathic pain‐related behavior and attenuates chronic dorsal horn neuron activation following cervical spinal cord injury

“…A number of groups have reported long-term decreases in GLT1 expression in various SCI animal models (Olsen et al 2010; Vera-Portocarrero et al 2002). We have also observed significant GLT1 down-regulation after thoracic (Lepore et al 2011a; Lepore et al 2011b) and cervical (Li et al 2014b) SCI, including in superficial dorsal horn in both mouse and rat models of cervical contusion that are associated with persistent neuropathic pain-related behavior (Putatunda et al 2014; Watson et al 2014). …”

“…We previously reported chronic increases in numbers of superficial dorsal horn neurons expressing the transcription factor, ΔFosB, following unilateral cervical contusion compared to uninjured laminectomy-only control mice and rats (Putatunda et al 2014; Watson et al 2014). ΔFosB is (1) a truncated splice version of the immediate early gene c-fos, (2) a molecular biomarker of chronic neuronal activation (Robison and Nestler 2011), and (3) is thought to transcriptionally mediate some of the long-term changes that result from chronic activation of pain transmission neurons (McClung et al 2004).…”

Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

“…Failure of long-term extrasynaptic glutamate clearance is suspected to be one major cause of secondary cell loss following SCI. Noteworthy, we and others demonstrated that astrocyte GLT1 was chronically lost at the injury epicenter following SCI but also downregulated in spinal cord regions distant from the lesion core [103][104][105][106] . Furthermore, experimental data showed that the newlygenerated astrocytes arising during the SCI repair phase lacked GLT1 expression, possibly compromising long-term astrocyte glutamate homeostasis [107] .…”