Investigating the Role of α2δ-1 in Spinal Dorsal Horn Neurons: A Step Forward in Understanding Neuropathic Pain

Neuropathic pain, a debilitating condition that arises from nerve damage, remains a significant challenge in clinical practice. Gabapentinoids, such as pregabalin, gabapentin, and mirogabalin, have emerged as widely prescribed drugs for neuropathic pain management. These drugs target α₂δ-1, a subunit of voltage-gated calcium channels, to inhibit calcium-mediated neurotransmitter release and alleviate neuropathic pain. However, the specific contribution of α₂δ-1 expressed in spinal dorsal horn (SDH) neurons to altered synaptic transmission and mechanical hypersensitivity following nerve injury has been unclear.

In a new study published in the Frontiers in Molecular Neuroscience by Dr. Keisuke Koga and Dr. Hidemasa Furue from Hyogo Medical University together with Dr. Kenta Kobayashi from National Institute for Physiological Sciences and Dr. Makoto Tsuda from Kyushu University and Dr. Kazufumi Kubota and Dr. Yutaka Kitano from Daiichi Sankyo Co., Ltd. sheds new light on the role of α₂δ-1 in SDH neurons and its impact on neuropathic pain. The researchers used advanced techniques to investigate the expression of α₂δ-1 in different types of SDH neurons and its contribution to mechanical hypersensitivity and altered spinal synaptic transmission after nerve injury.

The research team employed in situ hybridization to determine the colocalization of α₂δ-1 with specific neuronal markers. The researchers found that α₂δ-1 was primarily expressed in excitatory SDH neurons, marked by Slc17a6, an excitatory neuronal marker. It did not colocalize with Slc32a1, an inhibitory neuronal marker. This finding suggests that α₂δ-1 may play a role in modulating excitatory synaptic transmission in the SDH. To further investigate the function of α₂δ-1 in SDH neurons, the researchers utilized the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system for neuron-specific ablation of Cacna2d1, the gene encoding α₂δ-1. They demonstrated that SDH neuron-specific ablation of α₂δ-1 alleviated mechanical hypersensitivity observed after nerve injury. Additionally, the study revealed that electrical stimulation applied to the SDH evoked enhanced excitatory post-synaptic responses in a neuropathic pain model. These enhanced responses were significantly reduced by the application of mirogabalin, a potent α₂δ-1 inhibitor, and by SDH neuron-specific ablation of α₂δ-1. These results provide further evidence that α₂δ-1 expressed in SDH excitatory neurons facilitates spinal nociceptive synaptic transmission and contributes to the development of mechanical hypersensitivity after nerve injury.

The authors’ findings have significant implications for understanding the underlying mechanisms of neuropathic pain and the pharmacological effects of gabapentinoids. Previous studies have shown that α₂δ-1 modulates the current density and membrane trafficking of voltage-gated calcium channels. Furthermore, α₂δ-1 upregulation in dorsal root ganglion neurons after nerve injury enhances axonal transport of these channels to their central terminals in the SDH. While previous manipulations affecting α₂δ-1 expression or function targeted both SDH and dorsal root ganglion neurons, this study’s approach selectively manipulated α₂δ-1 expression in SDH neurons. This specificity provides valuable insights into the contribution of α₂δ-1 in SDH neurons to the neuropathic pain phenotype after nerve injury.

The authors highlighted the importance of α₂δ-1 selectivity among α₂δ subunits for both the development of neuropathic pain and the pharmacological effects of gabapentinoids. The differential expression patterns of α₂δ-1, α₂δ-2, and α₂δ-3 subunits in the SDH suggest distinct roles for these subunits in pain processing. The authors future studies will focus on elucidating the precise contributions of α₂δ-1 in different regions of the central nervous system to neuropathic pain and other psychological disorders resulting from nerve injury. Additionally, further investigations are warranted to explore the postsynaptic role of α₂δ-1 in pain facilitation after nerve injury.

The study by Dr. Keisuke Koga and colleagues represents an important step forward in understanding the role of α₂δ-1 in SDH neurons and its involvement in neuropathic pain. The research provides valuable insights into the mechanisms underlying gabapentinoid pharmacology and the selectivity of α₂δ-1 in mediating pain hypersensitivity after nerve injury. By shedding light on the specific contribution of α₂δ-1 in SDH neurons to altered synaptic transmission and mechanical hypersensitivity, this study enhances our understanding of neuropathic pain and lays the groundwork for the development of targeted therapeutic interventions. Research advances in this field has the potential to improve the lives of individuals suffering from neuropathic pain and advance our knowledge of pain processing in the nervous system.