神经肽1
神经病理性疼痛
痛觉超敏
痛觉过敏
药理学
医学
受体
脊髓
伤害感受器
血管内皮生长因子
化学
神经科学
内科学
麻醉
伤害
生物
血管内皮生长因子受体
作者
Harrison J. Stratton,Lisa Boinon,Kimberly Gomez,Laurent Martin,Paz Duran,Dongzhi Ran,Yuan Zhou,Shizhen Luo,Samantha Perez-Miller,Marcel Patek,Mohab Ibrahim,Amol Patwardhan,Aubin Moutal,Rajesh Khanna
出处
期刊:Pain
[Ovid Technologies (Wolters Kluwer)]
日期:2022-12-19
卷期号:164 (7): 1473-1488
被引量:1
标识
DOI:10.1097/j.pain.0000000000002850
摘要
In Brief Vascular endothelial growth factor A (VEGF-A) is a pronociceptive factor that causes neuronal sensitization and pain. We reported that blocking the interaction between the membrane receptor neuropilin 1 (NRP1) and VEGF-A–blocked VEGF-A–mediated sensory neuron hyperexcitability and reduced mechanical hypersensitivity in a rodent chronic neuropathic pain model. These findings identified the NRP1-VEGF-A signaling axis for therapeutic targeting of chronic pain. In an in-silico screening of approximately 480 K small molecules binding to the extracellular b1b2 pocket of NRP1, we identified 9 chemical series, with 6 compounds disrupting VEGF-A binding to NRP1. The small molecule with greatest efficacy, 4′-methyl-2′-morpholino-2-(phenylamino)-[4,5′-bipyrimidin]-6(1H)-one, designated NRP1-4, was selected for further evaluation. In cultured primary sensory neurons, VEGF-A enhanced excitability and decreased firing threshold, which was blocked by NRP1-4. In addition, NaV1.7 and CaV2.2 currents and membrane expression were potentiated by treatment with VEGF-A, and this potentiation was blocked by NRP1-4 cotreatment. Neuropilin 1-4 reduced VEGF-A–mediated increases in the frequency and amplitude of spontaneous excitatory postsynaptic currents in dorsal horn of the spinal cord. Neuropilin 1-4 did not bind to more than 300 G-protein-coupled receptors and receptors including human opioids receptors, indicating a favorable safety profile. In rats with spared nerve injury–induced neuropathic pain, intrathecal administration of NRP1-4 significantly attenuated mechanical allodynia. Intravenous treatment with NRP1-4 reversed both mechanical allodynia and thermal hyperalgesia in rats with L5/L6 spinal nerve ligation–induced neuropathic pain. Collectively, our findings show that NRP1-4 is a first-in-class compound targeting the NRP1-VEGF-A signaling axis to control voltage-gated ion channel function, neuronal excitability, and synaptic activity that curb chronic pain. NRP1-4 is a first-in-class compound uncoupling the neuropilin 1–vascular endothelial growth factor A signaling axis to reduce voltage-gated ion channel function, neuronal excitability, and synaptic activity that curbs chronic pain.
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