Chen Hanbin, Li Guanghong, Deng Lin, Li Shuli, Huang Songqiang, Lee Simon Ming-Yuen, Nie Xiaowei, Bian Jin-Song
Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
Biol Res. 2025 Jul 10;58(1):48. doi: 10.1186/s40659-025-00630-5.
Pain serves as a vital protective mechanism triggered by tissue damage. While NSAIDs and opioids offer relief, their prolonged usage is hindered by adverse effects. Developing analgesics with fewer side effects is crucial for effective pain treatment. The TRPV1 channel is a key target for pain relief, with its inhibitors effectively reducing hyperalgesia in animals. This research utilized virtual screening to identify TRPV1-selective natural compounds for potent analgesic properties.
The physcion exhibited the notable affinity for TRPV1 compared to the compounds examined. After conducting molecular dynamics simulations, physcion emerged as the compound demonstrating the highest binding affinity towards TRPV1, a finding corroborated by calcium imaging, which validated its inhibitory impact. Furthermore, physcion mitigated the stretch number in the acetic acid-induced stretching model, prolonged the latency period in the hot water tail-flick and hot plate assays, and heightened the pain withdrawal threshold lowered by complete Freund's adjuvant (CFA). Notably, physcion exerted a marked effect in ameliorating bone cancer-induced pain in the hot plate and von Frey tests. Additionally, physcion diminished the levels of inflammatory cytokines and the mRNA expression of both inflammatory and calcium-related genes in the CFA-induced murine model. Furthermore, physcion downregulated the expression of inflammatory genes induced by tumor necrosis factor-α (TNF-α) in RAW264.7 cells. The underlying mechanism potentially involves the suppression of the NF-κB and MAPK signaling cascades.
Our investigation underscores the potential of physcion as a promising candidate for analgesic therapy.
疼痛是由组织损伤触发的重要保护机制。虽然非甾体抗炎药（NSAIDs）和阿片类药物能缓解疼痛，但其长期使用会受到副作用的限制。开发副作用较少的镇痛药对有效治疗疼痛至关重要。瞬时受体电位香草酸亚型1（TRPV1）通道是缓解疼痛的关键靶点，其抑制剂可有效减轻动物的痛觉过敏。本研究利用虚拟筛选来鉴定具有强效镇痛特性的TRPV1选择性天然化合物。
与所检测的化合物相比，大黄素对TRPV1表现出显著的亲和力。进行分子动力学模拟后，大黄素成为对TRPV1具有最高结合亲和力的化合物，钙成像证实了这一发现，验证了其抑制作用。此外，大黄素减少了醋酸诱导的伸展模型中的伸展次数，延长了热水甩尾和热板试验中的潜伏期，并提高了完全弗氏佐剂（CFA）降低的疼痛退缩阈值。值得注意的是，大黄素在热板和von Frey试验中对改善骨癌引起的疼痛有显著效果。此外，大黄素降低了CFA诱导的小鼠模型中炎症细胞因子的水平以及炎症和钙相关基因的mRNA表达。此外，大黄素下调了RAW264.7细胞中肿瘤坏死因子-α（TNF-α）诱导的炎症基因的表达。潜在机制可能涉及对核因子κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）信号级联的抑制。
我们的研究强调了大黄素作为镇痛治疗有前景的候选药物的潜力。
