The enhanced release of inflammatory cytokines mediated by high mobility group box1 (HMGB1) leads to pain sensation, and has been implicated in the etiology of inflammatory pain. Paeonol (PAE), a major active phenolic component in Cortex Moutan, provides neuroprotective efficacy via exerting anti-inflammatory effect. However, the role and mechanism of PAE in inflammatory pain remain to be fully clarified. In this study, we showed that PAE treatment significantly ameliorated mechanical and thermal hyperalgesia of mice induced by complete Freund’s adjuvant (CFA). The analgesic effect of PAE administration was associated with suppressing the enhanced expression of HMGB1 as well as the downstream signaling molecules including toll-like receptor 4 (TLR4), the nuclear NF-κB p65, TNF-α and IL-1β after CFA insult in the anterior cingulate cortex (ACC), a key brain region responsible for pain processing. Furthermore, inhibition of HMGB1 activity by glycyrrhizin (GLY), an HMGB1 inhibitor, alleviated CFA-induced pain and also facilitated PAE-mediated analgesic effect in mice along with the decreased expression of TLR4, NF-κB p65, TNF-α and IL-1β upon CFA injury. Collectively, we showed PAE exerted analgesic effect through inhibiting the HMGB1/TLR4/NF-κB p65 pathway and subsequent generation of cytokines TNF-α and IL-1β in the ACC.

由高迁移率族 box1 (HMGB1) 介导的炎性细胞因子释放增强导致痛觉，并与炎性疼痛的病因有关。丹皮酚 (PAE) 是牡丹皮中的主要活性酚类成分，通过以下方式提供神经保护功效发挥抗炎作用。然而，PAE在炎症性疼痛中的作用和机制仍有待充分阐明。在这项研究中，我们发现 PAE 治疗显着改善了由完全弗氏佐剂 (CFA) 诱导的小鼠的机械和热痛觉过敏。PAE 给药的镇痛作用与抑制 HMGB1 以及下游信号分子包括 Toll 样受体 4 (TLR4)、核 NF-κB p65、TNF-α 和 IL-1β 的表达增强有关。前扣带皮层 (ACC)，负责处理疼痛的关键大脑区域。此外，HMGB1 抑制剂甘草甜素 (GLY) 抑制 HMGB1 活性可减轻 CFA 诱导的疼痛，并促进 PAE 介导的小鼠镇痛作用，同时降低 TLR4、NF-κB p65、CFA 损伤后的 TNF-α 和 IL-1β。总的来说，我们表明 PAE 通过抑制 HMGB1/TLR4/NF-κB p65 通路和随后在 ACC 中产生细胞因子 TNF-α 和 IL-1β 来发挥镇痛作用。