Voltage-gated calcium channel subunit α2δ-1 in spinal dorsal horn neurons contributes to aberrant excitatory synaptic transmission and mechanical hypersensitivity after peripheral nerve injury

Abstract

Neuropathic pain, an intractable pain symptom that occurs after nerve damage, is caused by the aberrant excitability of spinal dorsal horn (SDH) neurons. Gabapentinoids, the most commonly used drugs for neuropathic pain, inhibit spinal calcium-mediated neurotransmitter release by binding to α2δ-1, a subunit of voltage-gated calcium channels, and alleviate neuropathic pain. However, the exact contribution of α2δ-1 expressed in SDH neurons to the altered synaptic transmission and mechanical hypersensitivity following nerve injury is not fully understood. In this study, we investigated which types of SDH neurons express α2δ-1 and how α2δ-1 in SDH neurons contributes to the mechanical hypersensitivity and altered spinal synaptic transmission after nerve injury. Using in situ hybridization technique, we found that Cacna2d1, mRNA coding α2δ-1, was mainly colocalized with Slc17a6, an excitatory neuronal marker, but not with Slc32a1, an inhibitory neuronal marker in the SDH. To investigate the role of α2δ-1 in SDH neurons, we used clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system and showed that SDH neuron-specific ablation of Cacna2d1 alleviated mechanical hypersensitivity following nerve injury. We further found that excitatory post-synaptic responses evoked by electrical stimulation applied to the SDH were significantly enhanced after nerve injury, and that these enhanced responses were significantly decreased by application of mirogabalin, a potent α2δ-1 inhibitor, and by SDH neuron-specific ablation of Cacna2d1. These results suggest that α2δ-1 expressed in SDH excitatory neurons facilitates spinal nociceptive synaptic transmission and contributes to the development of mechanical hypersensitivity after nerve injury.

LncRNA 4930544M13Rik-201 regulates CACNA2D1 expression via interacting with hnRNPA2B1 to promote neuropathic pain following nerve injury

“…For instance, previous studies have reported a signi cant elevation in CACNA2D1 expression in the DRG and spinal cord following peripheral nerve injury [17,18]. Moreover, ablation of Cacna2d1 mRNA alleviated mechanical hypersensitivity following nerve injury [19]. Notably, in our prior investigations, we observed a signi cant upregulation of CACNA2D1 within the TG after inferior alveolar nerve injury, resulting in trigeminal NP.…”

Mirogabalin inhibits scratching behavior of spontaneous model mouse of atopic dermatitis

“…Intrathecal injection of MGB in a mouse model of neuropathic pain significantly suppressed mechanical allodynia, whereas in a rat model of inflammatory pain induced by formalin, it significantly suppressed flinches ( Komatsu et al, 2021 ; Oyama et al, 2021 ). Recently, in patch clamp recordings using spinal cord slices from a mouse model of peripheral nerve injury, MGB reduced the amplitude of EPSCs evoked by electrical stimulation of the deep layer in the SDH ( Koga et al, 2023 ). In addition, nociceptive and itch information generated in the periphery enters the SDH primarily via C fibers, and these pathways often overlap ( Dhand and Aminoff, 2014 ).…”

Memantine Inhibits Calcium-Permeable AMPA Receptors

“…We have demonstrated that α2δ-1 is essential for nerve injury-induced increases in CP-AMPARs (11). Given that α2δ-1 exhibits specific expression in VGluT2-expressing excitatory neurons within the spinal cord (41), we determined the potential effect of memantine on synaptic CP-AMPARs in genetically labeled spinal VGluT2 neurons of mice subjected to spared nerve injury.…”