rdHSV-CA8 非阿片类镇痛基因疗法通过激活 Kv7 电压门控钾通道降低躯体感觉神经元的兴奋性

IF 3.5 3区医学 Q2 NEUROSCIENCES

Frontiers in Molecular Neuroscience Pub Date : 2024-05-09 DOI:10.3389/fnmol.2024.1398839

Munal B. Kandel, Gerald Z. Zhuang, William F. Goins, Marco Marzulli, Mingdi Zhang, Joseph C. Glorioso, Yuan Kang, Alexandra E. Levitt, Wai-Meng Kwok, Roy C. Levitt, Konstantinos D. Sarantopoulos

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引用次数: 0

摘要

慢性疼痛很常见，但治疗效果不佳，因此开发安全有效的镇痛药成为当务之急。我们之前的数据表明，背根神经节（DRG）中碳酸酐酶-8（CA8）的表达是通过抑制神经元ER肌醇三磷酸受体-1（ITPR1），进而减少ER钙释放和降低细胞质游离钙来介导镇痛的，而ER钙释放和降低游离钙对神经元兴奋性的调节至关重要。本研究测试了携带 CA8 转基因（vHCA8）的新型 JDNI8 复制缺陷单纯疱疹-1 病毒载体（rdHSV）会降低初级传入神经兴奋性的假设。对小型 DRG 神经元的全细胞电流钳记录显示，vHCA8 转导会导致神经元过极化后（AHP）延长，而过极化后是神经元兴奋性的重要调节因子。特异性 Kv7 通道抑制剂 XE-991 可完全逆转这种 AHP 延长。电压钳记录表明，vHCA8感染的小DRG神经元通过Kv7通道产生效应。这些数据首次证明了 vHCA8 会激活 Kv7 通道，从而降低痛觉感受器神经元的兴奋性。如果在行为和临床上得到证实，这种兴奋性的抑制可能会在体内转化为非阿片类药物依赖的行为或临床镇痛。

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rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channels

Chronic pain is common and inadequately treated, making the development of safe and effective analgesics a high priority. Our previous data indicate that carbonic anhydrase-8 (CA8) expression in dorsal root ganglia (DRG) mediates analgesia via inhibition of neuronal ER inositol trisphosphate receptor-1 (ITPR1) via subsequent decrease in ER calcium release and reduction of cytoplasmic free calcium, essential to the regulation of neuronal excitability. This study tested the hypothesis that novel JDNI8 replication-defective herpes simplex-1 viral vectors (rdHSV) carrying a CA8 transgene (vHCA8) reduce primary afferent neuronal excitability. Whole-cell current clamp recordings in small DRG neurons showed that vHCA8 transduction caused prolongation of their afterhyperpolarization (AHP), an essential regulator of neuronal excitability. This AHP prolongation was completely reversed by the specific Kv7 channel inhibitor XE-991. Voltage clamp recordings indicate an effect via Kv7 channels in vHCA8-infected small DRG neurons. These data demonstrate for the first time that vHCA8 produces Kv7 channel activation, which decreases neuronal excitability in nociceptors. This suppression of excitability may translate in vivo as non-opioid dependent behavioral- or clinical analgesia, if proven behaviorally and clinically.

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来源期刊

Frontiers in Molecular Neuroscience NEUROSCIENCES-

CiteScore

5.70

自引率

2.10%

发文量

669

审稿时长

14 weeks

期刊介绍： Frontiers in Molecular Neuroscience is a first-tier electronic journal devoted to identifying key molecules, as well as their functions and interactions, that underlie the structure, design and function of the brain across all levels. The scope of our journal encompasses synaptic and cellular proteins, coding and non-coding RNA, and molecular mechanisms regulating cellular and dendritic RNA translation. In recent years, a plethora of new cellular and synaptic players have been identified from reduced systems, such as neuronal cultures, but the relevance of these molecules in terms of cellular and synaptic function and plasticity in the living brain and its circuits has not been validated. The effects of spine growth and density observed using gene products identified from in vitro work are frequently not reproduced in vivo. Our journal is particularly interested in studies on genetically engineered model organisms (C. elegans, Drosophila, mouse), in which alterations in key molecules underlying cellular and synaptic function and plasticity produce defined anatomical, physiological and behavioral changes. In the mouse, genetic alterations limited to particular neural circuits (olfactory bulb, motor cortex, cortical layers, hippocampal subfields, cerebellum), preferably regulated in time and on demand, are of special interest, as they sidestep potential compensatory developmental effects.