Spinal Dorsal Horn Calcium Channel α₂δ-1 Subunit Upregulation Contributes to Peripheral Nerve Injury-Induced Tactile Allodynia

Abstract

Peripheral nerve injury induces upregulation of the calcium channel ␣ 2 ␦-1 structural subunit in dorsal root ganglia (DRG) and dorsal spinal cord of spinal nerve-ligated rats with neuropathic pain, suggesting a role of the calcium channel ␣ 2 ␦-1 subunit in central sensitization. To investigate whether spinal dorsal horn ␣ 2 ␦-1 subunit upregulation derives from increased DRG ␣ 2 ␦-1 subunit and plays a causal role in neuropathic pain development, we examined spinal dorsal horn ␣ 2 ␦-1 subunit expression with or without dorsal rhizotomy in spinal nerve-ligated rats and its correlation with tactile allodynia, a neuropathic pain state defined as reduced thresholds to nonnoxious tactile stimulation. We also examined the effects of intrathecal ␣ 2 ␦-1 antisense oligonucleotides on ␣ 2 ␦-1 subunit expression and neuropathic allodynia in the nerve-ligated rats. Our data indicated that spinal nerve injury resulted in time-dependent ␣ 2 ␦-1 subunit upregulation in the spinal dorsal horn that correlated temporally with neuropathic allodynia development and maintenance. Dorsal rhizotomy diminished basal level expression and blocked injury-induced expression of the spinal dorsal horn ␣ 2 ␦-1 subunit and reversed injury-induced tactile allodynia. In addition, intrathecal ␣ 2 ␦-1 antisense oligonucleotides blocked injury-induced dorsal horn ␣ 2 ␦-1 subunit upregulation and diminished tactile allodynia. These findings indicate that ␣ 2 ␦-1 subunit basal expression occurs presynaptically and postsynaptically in spinal dorsal horn. Nerve injury induces mainly presynaptic ␣ 2 ␦-1 subunit expression that derives from increased ␣ 2 ␦-1 subunit in injured DRG neurons. Thus, changes in presynaptic ␣ 2 ␦-1 subunit expression contribute to injury-induced spinal neuroplasticity and central sensitization that underlies neuropathic pain development and maintenance.

Gabapentinoid Insensitivity after Repeated Administration is Associated with Down-Regulation of the α2δ-1 Subunit in Rats with Central Post-Stroke Pain Hypersensitivity

“…The von Willebrand factor-A domain is involved in trafficking the VGCC a 2 d-1 subunit to the plasma membrane [23,65,66]. Knock-down of a 2 d-1 reduces pain hypersensitivity in an animal model of nerve injury [30]. It has also been confirmed that the antinociceptive and anti-allodynic effects of GBP and pregabalin are due to disruption of trafficking of the VGCC a 2 d-1 subunit to the presynaptic terminal membrane induced by nerve injury [25][26][27]32].…”

“…Experimentally, expression of a 2 d-1, but not a 2 d-2 (another binding site of GBP), is significantly increased in both the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord in animal models of peripheral neuropathic pain. This up-regulation is thought to contribute to the development of allodynia and hyperalgesia [28][29][30][31]. It has thus been proposed that gabapentinoids alleviate neuropathic pain by blocking the trafficking of a 2 d-1 to the presynaptic terminals of DRG neurons and this subsequently leads to reduced Ca 2?…”

Dor neuropática: aspectos neuroquímicos

“…A redução ou a falha da função desses receptores podem levar a hiperexcitabilidade neuronal do nervo lesado. Também, pode haver aumento das subunidades de canais de cálcio tipo α2δ no gânglio da raiz dorsal e na medula espinal 13 , fato que provoca a liberação de neurotransmissores excitatórios. A alteração fenotípica de fibras Aδ na dor neuropática causaria, de maneira semelhante, a liberação pré-sináptica de substância P facilitando a sensibilização do corno dorsal da medula espinal.…”

“…The reduction or failure of the function of those receptors can lead to neuronal hyperexcitability in the damaged nerve. Calcium channels α2δ subunits in the dorsal root ganglion and in the spinal cord can also be increased 13 , which cause the release of excitatory neurotransmitters. The phenotypic change of Aδ fibers in neuropathic pain would similarly cause the presynaptic release of substance P facilitating sensitization of the dorsal horn of the spinal cord.…”

Les canaux calciques dépendants du voltage au cœur de la douleur

“…Cette surexpression des sous-unités α 2 δ 1 n'affecte ni l'expression de la sousunité α 1B , ni celle des sous-unités β [37]. L'injection intrathécale d'oligonucléotides antisens, visant à diminuer le niveau d'expression des sous-unités α 2 δ 1 , confère aux animaux un effet anti-allodynie [38]. De plus, l'injection intrathécale de gabapentine (un anticonvulsif et antiépileptique) (Tableau II), capable d'interagir in vitro avec les sous-unités α 2 δ, diminue également les douleurs allodyniques sur ces modèles animaux.…”