Chen Hanbin, Li Guanghong, Deng Lin, Xu Nan, Lee Simon Ming-Yuen, Nie Xiaowei, Bian Jin-Song
Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
Front Pharmacol. 2025 Jun 10;16:1585181. doi: 10.3389/fphar.2025.1585181. eCollection 2025.
Pain is a complex phenomenon involving physiological and psychological responses to noxious stimuli. Long-term opioid or NSAID use leads to reduced efficacy and tolerance. Initially a thermosensitive receptor, TRPV1 is increasingly recognized as a target for analgesic intervention.
Our investigation is focused on the exploration of novel TRPV1 antagonists derived from natural sources through computational screening methodologies, aiming to assess their efficacy as analgesic agents.
Among the compounds screened, a promising TRPV1 antagonist named pinocembrin-7-o-3-o-galloyl-4-6-hexahydroxydiphenoyl-beta-d-glucoside (PINO) has exhibited superior stability in its interaction with TRPV1 through virtual screening and molecular dynamics simulation. A dosage of 20 mg/kg of PINO had been shown to reduce the writhing response in acetic acid-induced mice, elevate the thermal pain threshold in the hot water tail-flick and hot plate assays, and concurrently increase the mechanical pain threshold in CFA-induced inflammatory pain models in mice. Moreover, in a murine Lewis lung carcinoma cell line LL-induced bone cancer pain model, PINO also effectively raised the thermal and mechanical pain thresholds in mice. Furthermore, PINO had been found to attenuate the production and gene expression of pro-inflammatory cytokines. The underlying mechanism was attributed to the suppression of NF-κB and MAPK signaling cascades.
This innovative compound represents a prospective avenue for the management of acute, chronic, and bone cancer pain, providing a viable alternative analgesic option for individuals suffering from such conditions.
疼痛是一种复杂的现象，涉及对有害刺激的生理和心理反应。长期使用阿片类药物或非甾体抗炎药会导致疗效降低和耐受性。瞬时受体电位香草酸亚型1（TRPV1）最初是一种热敏受体，现在越来越被认为是镇痛干预的靶点。
我们的研究重点是通过计算筛选方法探索源自天然来源的新型TRPV1拮抗剂，旨在评估它们作为镇痛剂的疗效。
在筛选的化合物中，一种有前景的TRPV1拮抗剂，名为松属素-7-O-3-O-没食子酰基-4,6-六羟基二苯甲酰基-β-D-葡萄糖苷（PINO），通过虚拟筛选和分子动力学模拟，在与TRPV1的相互作用中表现出卓越的稳定性。已证明20mg/kg的PINO剂量可减少醋酸诱导的小鼠扭体反应，提高热水甩尾和热板试验中的热痛阈值，并同时提高小鼠在完全弗氏佐剂（CFA）诱导的炎症性疼痛模型中的机械痛阈值。此外，在小鼠Lewis肺癌细胞系LL诱导的骨癌疼痛模型中，PINO也有效提高了小鼠的热痛和机械痛阈值。此外，还发现PINO可减轻促炎细胞因子的产生和基因表达。其潜在机制归因于对核因子κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）信号级联的抑制。
这种创新化合物代表了一种用于治疗急性、慢性和骨癌疼痛的潜在途径，为患有此类疾病的个体提供了一种可行的替代镇痛选择。
