Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Physalin F via Block of CaV2.3 (R-Type) and CaV2.2 (N-Type) Voltage-Gated Calcium Channels
Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Physalin F via Block of CaV2.3 (R-Type) and CaV2.2 (N-Type) Voltage-Gated Calcium Channels
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小分子天然产物 Physalin F 通过阻断 CaV2.3（R 型）和 CaV2.2（N 型）电压门控钙通道逆转周围神经性疼痛
DOI：
10.1021/acschemneuro.9b00166
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发表时间：
2019-06-01
影响因子：
5
通讯作者：
Khanna, Rajesh
中科院分区：
文献类型：
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作者：
Shan, Zhiming;Cai, Song;Khanna, Rajesh
慢性疼痛是一种影响全球五分之一人口的疾病，目前还没有普遍有效的治疗方法。过度依赖阿片类药物治疗慢性疼痛，尽管它们改善功能的能力很差，导致了全国性的阿片类药物危机。2018年，美国国立卫生研究院启动了一项帮助结束成瘾的长期计划，以刺激发现和验证新的目标和机制，以开发替代的非成瘾治疗方案。具有药用特性的植物化学物质长期以来一直用于世界各地的各种治疗。从酸浆（Physalis acutifolia）（茄科（Solanaceae））草本植物中分离的天然产物酸浆素F在炎性疼痛模型中表现出抗伤害感受作用，与其抗炎和免疫调节活性的早期报道一致。然而，酸浆苦素F的作用靶点仍然未知。在这里，利用全细胞和切片电生理学、竞争结合测定和神经性疼痛的实验模型，我们发现了酸浆素F抗伤害作用的分子靶点。我们发现酸浆素F（i）阻断背根神经节（DRG）神经元中的CaV2.3（R型）和CaV2.2（N型）电压门控钙通道，（ii）不影响CaV3（T型）电压门控钙通道或电压门控钠或钾通道，（iii）不结合G蛋白偶联阿片受体，（iv）抑制脊髓切片中自发兴奋性突触后电流（EPSC）的频率，和（v）逆转紫杉醇诱导的周围神经病变和脊神经结扎模型中的触觉超敏性。将CaV2.2确定为酸浆素F的分子靶点可能会刺激其作为机制研究的工具，并将其定位为未来合成化合物的结构模板。
No universally efficacious therapy exists for chronic pain, a disease affecting one-fifth of the global population. An overreliance on the prescription of opioids for chronic pain despite their poor ability to improve function has led to a national opioid crisis. In 2018, the NIH launched a Helping to End Addiction Long-term plan to spur discovery and validation of novel targets and mechanisms to develop alternative nonaddictive treatment options. Phytochemicals with medicinal properties have long been used for various treatments worldwide. The natural product physalin F, isolated from the Physalis acutifolia (family: Solanaceae) herb, demonstrated antinociceptive effects in models of inflammatory pain, consistent with earlier reports of its anti-inflammatory and immunomodulatory activities. However, the target of action of physalin F remained unknown. Here, using whole-cell and slice electrophysiology, competition binding assays, and experimental models of neuropathic pain, we uncovered a molecular target for physalin F's antinociceptive actions. We found that physalin F (i) blocks CaV2.3 (R-type) and CaV2.2 (N-type) voltage-gated calcium channels in dorsal root ganglion (DRG) neurons, (ii) does not affect CaV3 (T-type) voltage-gated calcium channels or voltage-gated sodium or potassium channels, (iii) does not bind G-protein coupled opioid receptors, (iv) inhibits the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in spinal cord slices, and (v) reverses tactile hypersensitivity in models of paclitaxel-induced peripheral neuropathy and spinal nerve ligation. Identifying CaV2.2 as a molecular target of physalin F may spur its use as a tool for mechanistic studies and position it as a structural template for future synthetic compounds.