Nguyen, D; Deng, P; Matthews, EA; Kim, DS; Feng, GP; Dickenson, AH; Xu, ZC; Nguyen, D; Deng, P; Matthews, EA; Kim, DS; Feng, GP; Dickenson, AH; Xu, ZC; Luo, ZD; - view fewer (2009) Enhanced pre-synaptic glutamate release in deep-dorsal horn contributes to calcium channel alpha-2-delta-1 protein-mediated spinal sensitization and behavioral hypersensitivity. Molecular Pain , 5 , Article 6. 10.1186/1744-8069-5-6.

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Abstract

Nerve injury-induced expression of the spinal calcium channel alpha-2-delta-1 subunit (Ca-v alpha(2)delta(1)) has been shown to mediate behavioral hypersensitivity through a yet identified mechanism. We examined if this neuroplasticity modulates behavioral hypersensitivity by regulating spinal glutamatergic neurotransmission in injury-free transgenic mice overexpressing the Ca-v alpha(2)delta(1) proteins in neuronal tissues. The transgenic mice exhibited hypersensitivity to mechanical stimulation (allodynia) similar to the spinal nerve ligation injury model. Intrathecally delivered antagonists for N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, but not for the metabotropic glutamate receptors, caused a dose-dependent allodynia reversal in the transgenic mice without changing the behavioral sensitivity in wild-type mice. This suggests that elevated spinal Ca-v alpha(2)delta(1) mediates allodynia through a pathway involving activation of selective glutamate receptors. To determine if this is mediated by enhanced spinal neuronal excitability or pre-synaptic glutamate release in deep-dorsal horn, we examined wide-dynamic-range (WDR) neuron excitability with extracellular recording and glutamate-mediated excitatory postsynaptic currents with whole-cell patch recording in deep-dorsal horn of the Ca-v alpha(2)delta(1) transgenic mice. Our data indicated that overexpression of Ca-v alpha(2)delta(1) in neuronal tissues led to increased frequency, but not amplitude, of miniature excitatory post synaptic currents mediated mainly by AMPA/kainate receptors at physiological membrane potentials, and also by NMDA receptors upon depolarization, without changing the excitability of WDR neurons to high intensity stimulation. Together, these findings support a mechanism of Ca-v alpha(2)delta(1)-mediated spinal sensitization in which elevated Ca-v alpha(2)delta(1) causes increased pre-synaptic glutamate release that leads to reduced excitation thresholds of post-synaptic dorsal horn neurons to innocuous stimuli. This spinal sensitization mechanism may mediate at least partially the neuropathic pain states derived from increased pre-synaptic Ca-v alpha(2)delta(1) expression.

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