Bogomoletz Institute of Physiology, 01024 Kyiv, Ukraine.
Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Int J Mol Sci. 2023 Jan 25;24(3):2341. doi: 10.3390/ijms24032341.
The dorsal horn (DH) neurons of the spinal cord play a critical role in nociceptive input integration and processing in the central nervous system. Engaged neuronal classes and cell-specific excitability shape nociceptive computation within the DH. The DH hyperexcitability (central sensitisation) has been considered a fundamental mechanism in mediating nociceptive hypersensitivity, with the proven role of Ca-permeable AMPA receptors (AMPARs). However, whether and how the DH hyperexcitability relates to changes in action potential (AP) parameters in DH neurons and if Ca-permeable AMPARs contribute to these changes remain unknown. We examined the cell-class heterogeneity of APs generated by DH neurons in inflammatory pain conditions to address these. Inflammatory-induced peripheral hypersensitivity increased DH neuronal excitability. We found changes in the AP threshold and amplitude but not kinetics (spike waveform) in DH neurons generating sustained or initial bursts of firing patterns. In contrast, there were no changes in AP parameters in the DH neurons displaying a single spike firing pattern. Genetic knockdown of the molecular mechanism responsible for the upregulation of Ca-permeable AMPARs allowed the recovery of cell-specific AP changes in peripheral inflammation. Selective inhibition of Ca-permeable AMPARs in the spinal cord alleviated nociceptive hypersensitivity, both thermal and mechanical modalities, in animals with peripheral inflammation. Thus, Ca-permeable AMPARs contribute to shaping APs in DH neurons and nociceptive hypersensitivity. This may represent a neuropathological mechanism in the DH circuits, leading to aberrant signal transfer to other nociceptive pathways.
脊髓背角（DH）神经元在中枢神经系统中对伤害性传入信息的整合和处理起着关键作用。参与的神经元类型和细胞特异性兴奋性决定了 DH 中的伤害性计算。DH 的过度兴奋（中枢敏化）被认为是介导伤害性过敏的基本机制，钙通透性 AMPA 受体（AMPAR）的作用已得到证实。然而，DH 的过度兴奋是否以及如何与 DH 神经元中动作电位（AP）参数的变化相关，以及钙通透性 AMPAR 是否有助于这些变化仍然未知。我们研究了炎症性疼痛条件下 DH 神经元产生的 AP 的细胞类型异质性，以解决这些问题。炎症引起的外周过敏会增加 DH 神经元的兴奋性。我们发现，在产生持续或初始爆发式放电模式的 DH 神经元中，AP 阈值和幅度发生变化，但不应期（尖峰波形）没有变化。相比之下，在显示单尖峰放电模式的 DH 神经元中，AP 参数没有变化。负责钙通透性 AMPAR 上调的分子机制的基因敲低允许恢复外周炎症中细胞特异性 AP 变化。在有外周炎症的动物中，选择性抑制脊髓中的钙通透性 AMPAR 可减轻热和机械两种方式的伤害性过敏。因此，钙通透性 AMPAR 有助于塑造 DH 神经元中的 AP 和伤害性过敏。这可能代表 DH 回路中的一种神经病理学机制，导致异常信号传递到其他伤害性途径。
