Ivasiuk Arsentii, Matvieienko Maksym, Kononenko Nikolai I, Duzhyy Dmytro E, Korogod Sergiy M, Voitenko Nana, Belan Pavel
Department of Molecular Biophysics, Bogomoletz Institute of Physiology of NAS of Ukraine, 01024 Kyiv, Ukraine.
Department of Sensory Signaling, Bogomoletz Institute of Physiology of NAS of Ukraine, 01024 Kyiv, Ukraine.
Biomolecules. 2023 Aug 28;13(9):1320. doi: 10.3390/biom13091320.
The development of pain symptoms in peripheral diabetic neuropathy (PDN) is associated with the upregulation of T-type Ca channels (T-channels) in the soma of nociceptive DRG neurons. Moreover, a block of these channels in DRG neurons effectively reversed mechanical and thermal hyperalgesia in animal diabetic models, indicating that T-channel functioning in these neurons is causally linked to PDN. However, no particular mechanisms relating the upregulation of T-channels in the soma of nociceptive DRG neurons to the pathological pain processing in PDN have been suggested. Here we have electrophysiologically identified voltage-gated currents expressed in nociceptive DRG neurons and developed a computation model of the neurons, including peripheral and central axons. Simulations showed substantially stronger sensitivity of neuronal excitability to diabetes-induced T-channel upregulation at the normal body temperature compared to the ambient one. We also found that upregulation of somatic T-channels, observed in these neurons under diabetic conditions, amplifies a single action potential invading the soma from the periphery into a burst of multiple action potentials further propagated to the end of the central axon. We have concluded that the somatic T-channel-dependent amplification of the peripheral nociceptive input to the spinal cord demonstrated in this work may underlie abnormal nociception at different stages of diabetes development.
外周糖尿病性神经病变（PDN）中疼痛症状的发展与伤害性背根神经节（DRG）神经元胞体中T型钙通道（T通道）的上调有关。此外，阻断DRG神经元中的这些通道可有效逆转动物糖尿病模型中的机械性和热痛觉过敏，这表明这些神经元中T通道的功能与PDN存在因果关系。然而，尚未有人提出将伤害性DRG神经元胞体中T通道的上调与PDN中的病理性疼痛处理相关联的具体机制。在此，我们通过电生理学方法鉴定了伤害性DRG神经元中表达的电压门控电流，并建立了包括外周和中枢轴突的神经元计算模型。模拟结果表明，与环境温度相比，在正常体温下神经元兴奋性对糖尿病诱导的T通道上调的敏感性显著增强。我们还发现，在糖尿病条件下这些神经元中观察到的胞体T通道上调，会将从外周侵入胞体的单个动作电位放大为一串多个动作电位，并进一步传播至中枢轴突末端。我们得出结论，这项研究中所证明的脊髓外周伤害性输入的胞体T通道依赖性放大可能是糖尿病发展不同阶段异常伤害感受的基础。
