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Abstract
Spinal cord injury often leads to central neuropathic pain syndromes, such as allodynic and hyperalgesic behaviors. Electrophysiologically, spinal dorsal horn neurons show enhanced activity to non-noxious and noxious stimuli as well as increased spontaneous activity following spinal cord injury, which often called hyperexcitability or central sensitization. Under hyperexcitable states, spinal neurons lose their ability of discrimination and encoding somatosensory information followed by abnormal somatosensory recognition to non-noxious and noxious stimuli. In the present review, we summarize a variety of pathophysiological mechanisms of neuronal hyperexcitability for treating or preventing central neuropathic pain syndrome following spinal cord injury.
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Figure 1.
Hyperexcitability of lumbar spinal dorsal horn neurons following low thoracic spinal cord injury. All phenotypes of lumbar spinal dorsal horn neurons showed significantly increased evoked activity in response to mechanical stimuli applied on the receptive field compared to sham controls. Low threshold (LT) neurons showed significant increase of brush evoked activity whereas high threshold (HT) neurons showed significantly increased activity to pressure and pinch stimuli, respectively. Wide dynamic range (WDR) neurons showed significantly increased activity to all three different mechanical stimuli. Br: brush, Pr: pressure, Pi: pinch stimuli. ∗P<0.05.
Figure 2.
Attenuation of neuronal hyperexcitability and mechanical allodynia by γ-aminobutyric acid (GABA) receptor agonist. (A) shows typical histograms of wide dynamic range (WDR) neurons in response to brush, pressure and pinch stimuli applied on the peripheral receptive field. (B) shows attenuation of WDR activity by topical application of baclofen (GABAB receptor agonist) in the lumbar spinal dorsal horn following low thoracic spinal cord injury. (C) shows attenuation of mechanical allodynia by intrathecal application of baclofen following spinal cord injury. ∗P<0.05 compared to control values; #P<0.05 compared to pre-drug (before) values. Modified from Gwak et al. (2006).
Figure 3.
Intracellular signaling pathway for neuronal hyperexcitability. Following spinal cord injury, massive influx of calcium ions through calcium-permeable channels into cytoplasm initiates activation of mitogen-associated protein kinase (MAPK) family followed by activation of transcription factors, which result in altered target protein expression, such as phosphorylation of receptors and ion channels in the membrane. Activation of ion channels and receptors directly contributed to neuronal hyperexcitability. This positive feedback maintains persistent hyperexcitability of spinal dorsal horn neurons following spinal cord injury.
Table 1.
Proportional changes of thalamic VPL neurons following spinal hemisection injury. The sham group showed higher incidence of low threshold (LT) neurons than both wide dynamic range (WDR) and high threshold (HT) neurons. After hemisection, both ipsilateral and contralateral sides of thalamic VPL neurons showed higher incidences of WDR neurons than LT neurons, respectively. No HT neurons were observed in the rats with spinal cord injury (hemisection). Modified from Gwak et al. (2010)
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