Neuronal Hyperexcitability: A Substrate for Central Neuropathic Pain After Spinal Cord Injury

Gwak, Young Seob; Hulsebosch, Claire E.

doi:10.1007/s11916-011-0186-2

Cited by 86 publications

(62 citation statements)

References 48 publications

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“…However, we and others consistently reported that bilateral spinal cord injuries, such as spinal contusion injury, produce mechanical allodynia in both hindpaws, and hyperexcitability of spinal dorsal horn neurons and thalamic VPL neurons, suggesting that STTs, and not DC-MLs, are critical contributors to neuropathic pain following spinal contusion injury. 27,28 Taken together, the present data suggest that the intact (contralateral) side of the spinal dorsal horn mediates bilaterally-enhanced nociceptive transmissions to the gracile regions, which result in mechanical allodynia in the hindpaws and hyperexcitability of the gracile neurons following spinal hemisection. 29 However, the neuroanatomical and neurochemical changes in both the supraspinal regions and gracile neurons following spinal hemisection require further study.…”

Section: Figsupporting

confidence: 56%

Gracile Neurons Contribute to the Maintenance of Neuropathic Pain in Peripheral and Central Neuropathic Models

Kim

Wang

Gwak

2012

Journal of Neurotrauma

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In the present study, we compared the roles of gracile neurons in mechanically-induced neuropathic pain caused by spinal injury and L5 spinal nerve ligation in rats. Behavioral and electrophysiological methods were used to measure mechanical allodynia in the hindpaws, and excitability of the gracile neurons in the medulla, respectively. In the spinal hemisection and spinal contusion models, mechanical allodynia developed in both hindpaws and lasted over a month. Three weeks following the hemisection, gracile neurons identified as wide-dynamic-range (WDR) and low-threshold (LT) neurons, showed increased neuronal activity to non-noxious mechanical stimuli compared to control groups, whereas the spinal contusion groups did not show evoked activity (*p<0.05). A lesion of the gracile nucleus partially reversed the existing mechanical allodynia in both hindpaws compared to prior to the injury in the hemisection group, whereas the spinal contusion groups did not show significant changes (*p<0.05). In the spinal nerve ligation model, mechanical allodynia developed at the ipsilateral (injured) side of the hindpaw. In addition, WDR neuronal activity at the ipsilateral gracile neurons showed a significant increase with non-noxious mechanical stimuli, whereas the LT neurons did not show significant changes (*p<0.05). Similarly to the hemisection model, a lesion of the gracile nucleus attenuated the mechanical allodynia in spinal nerve ligation models. The present data suggest that gracile neurons contribute to the maintenance of non-noxious mechanically-induced neuropathic pain in both hemisection- and ligation-induced neuropathic pain in rats.

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Section: Figsupporting

confidence: 56%

Gracile Neurons Contribute to the Maintenance of Neuropathic Pain in Peripheral and Central Neuropathic Models

Kim

Wang

Gwak

2012

Journal of Neurotrauma

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“…Central sensitization of second order spinothalamic tract (STT) neurons in the superficial laminae of the dorsal horn is one major mechanism implicated in the pathogenesis of neuropathic pain (Gwak and Hulsebosch, 2011b). These changes can be chronic, resulting in the persistence of neuropathic pain.…”

Section: Resultsmentioning

confidence: 99%

“…Hyperexcitability of dorsal horn pain projection neurons (“central sensitization”) is a major substrate for neuropathic pain following SCI (Gwak and Hulsebosch, 2011b). This includes decreased threshold for activation (i.e.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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.

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“…Neuron hyper-excitability is an essential component of many disorders of the central nervous system (Curatolo et al, 2001), and also plays a role in the molecular basis of addiction (Koob & Le Moal, 2001) and autoimmune disorders (Hart et al, 2002). In particular, it produces enhanced pain transmission in the spinal dorsal horn after spinal cord injury (Gwak & Hulsebosch, 2011). Recently, the SK3 ion channel has gained attention as a new therapeutic target for disorders involving neuron hyper-excitability (Schlichter et al, 2010).…”

Section: Potential Host Receptors Of Na-asp-2mentioning

confidence: 99%

Probing the equatorial groove of the hookworm protein and vaccine candidate antigen, Na-ASP-2

Mason

Tribolet

Simon

et al. 2014

The International Journal of Biochemistry & Cell Biology

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Hookworm activation-associated secreted proteins can be structurally classified into at least three different groups. The hallmark feature of Group 1 activation-associated secreted proteins is a prominent equatorial groove, which is inferred to form a ligand binding site. Furthermore, a conserved tandem histidine motif is located in the centre of the groove and believed to provide or support a yet to be determined catalytic activity. Here, we report three-dimensional crystal structures of Na-ASP-2, an L3-secreted activationassociated secreted protein from the human hookworm Necator americanus, which demonstrate transition metal binding ability of the conserved tandem histidine motif. We further identified moderate phosphohydrolase activity of recombinant Na-ASP-2, which relates to the tandem histidine motif. By panning a random 12-mer peptide phage library, we identified a peptide with high similarity to the human calcium-activated potassium channel SK3, and confirm binding of the synthetic peptide to recombinant Na-ASP-2 by differential scanning fluorimetry. Potential binding modes of the peptide to Na-ASP-2 were studied by molecular dynamics simulations which clearly identify a preferred topology of the Na-ASP-2:SK3 peptide complex. KeywordsActivation-associated secreted proteins, Host-parasite interactions, Pathogenesis-related proteins, Protein structure, SCP/TAPS proteins Database Coordinates and structure factors have been deposited with the PDB, accession numbers 4nui, 4nuk, 4nun and 4nuo.

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Neuronal Hyperexcitability: A Substrate for Central Neuropathic Pain After Spinal Cord Injury

Cited by 86 publications

References 48 publications

Gracile Neurons Contribute to the Maintenance of Neuropathic Pain in Peripheral and Central Neuropathic Models

Gracile Neurons Contribute to the Maintenance of Neuropathic Pain in Peripheral and Central Neuropathic Models

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

Probing the equatorial groove of the hookworm protein and vaccine candidate antigen, Na-ASP-2

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