Hashemi Mojdeh, Raouf Fatemeh Hosseini, Dogani Manijeh, Shahsavari Fatemeh, Abasnejad Mehdi, Esmaili-Mahani Saeed, Khezri Amin, Mirmohammadi Hesam, Dianat Omid
Department of Oral and Maxillofascial Surgery, School of Dentistry, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran.
Int Endod J. 2025 Oct;58(10):1644-1658. doi: 10.1111/iej.14267. Epub 2025 Jul 29.
Orofacial pain, characterized by discomfort originating from areas such as the tooth pulp, trigeminal nerve and temporomandibular joint, poses substantial challenges in dentistry. Notably, pulpal and periapical pain profoundly impact the quality of life for affected individuals. Recent studies have highlighted a concerning association between pulpal pain and cognitive dysfunction, highlighting the intricate interplay between sensory distress and cognitive processes. Naringenin, a natural flavonoid, has garnered attention for its diverse physiological effects, including pain modulation. This investigation aims to elucidate the therapeutic potential of naringenin in mitigating capsaicin-induced pulpal pain and concomitant cognitive impairments. Additionally, we endeavour to unravel the underlying molecular mechanisms responsible for these observed effects, thereby contributing to a deeper understanding of naringenin's therapeutic utility in the management of orofacial pain syndromes.
Pulpal pain induction was achieved through intrapulpal injection of capsaicin (100 μg) in rat subjects. Central administration of naringenin was carried out at doses of 5, 10 and 15 μg per rat. Assessment of learning and memory performance was conducted using the Morris water maze task. Evaluation of inflammatory cytokine expression levels, including TNF-α, IL-1α, IL-1β, COX-2 and IL-6, as well as BDNF and TrkB expression, was performed using real-time PCR analysis.
Capsaicin administration resulted in a notable escalation of nociceptive responses alongside a concurrent decrement in cognitive function within the experimental rat model. Molecular analysis unveiled an upregulation of inflammatory cytokines coupled with a downregulation of BDNF and TrkB expression levels within the hippocampal region following pulpal pain induction. Remarkably, naringenin administration demonstrated a palliative effect against capsaicin-induced pain sensitivity and cognitive impairments, while also attenuating alterations in the aforementioned gene expressions induced by pain stimuli.
Naringenin appears to exert decreasing effects on both dental pain and pain-induced cognitive deficits, likely mediated through its ability to attenuate neuroinflammation and enhance growth factor signalling pathways. Consequently, it emerges as a promising natural therapeutic agent for the management of pain and associated cognitive impairments. Moreover, the intertwined neural pathways governing cognition and pain processing further underscore the complexity of orofacial pain syndromes.
口腔面部疼痛源于牙髓、三叉神经和颞下颌关节等部位，给牙科治疗带来了巨大挑战。值得注意的是，牙髓和根尖周疼痛严重影响患者的生活质量。最近的研究强调了牙髓疼痛与认知功能障碍之间令人担忧的关联，突出了感觉困扰与认知过程之间的复杂相互作用。柚皮素是一种天然黄酮类化合物，因其多种生理作用，包括疼痛调节作用而受到关注。本研究旨在阐明柚皮素在减轻辣椒素诱导的牙髓疼痛及伴随的认知障碍方面的治疗潜力。此外，我们努力揭示导致这些观察结果的潜在分子机制，从而更深入地了解柚皮素在口腔面部疼痛综合征管理中的治疗效用。
通过向大鼠牙髓内注射辣椒素（100μg）诱导牙髓疼痛。以每只大鼠5、10和15μg的剂量对柚皮素进行中枢给药。使用莫里斯水迷宫任务评估学习和记忆表现。采用实时PCR分析评估炎性细胞因子表达水平，包括肿瘤坏死因子-α（TNF-α）、白细胞介素-1α（IL-1α）、白细胞介素-1β（IL-1β）、环氧化酶-2（COX-2）和白细胞介素-6（IL-6），以及脑源性神经营养因子（BDNF）和酪氨酸激酶受体B（TrkB）的表达。
在实验大鼠模型中，注射辣椒素导致伤害性反应显著增强，同时认知功能下降。分子分析显示，牙髓疼痛诱导后，海马区炎性细胞因子上调，BDNF和TrkB表达水平下调。值得注意的是，给予柚皮素对辣椒素诱导的疼痛敏感性和认知障碍具有缓解作用，同时也减轻了疼痛刺激引起的上述基因表达变化。
柚皮素似乎对牙齿疼痛和疼痛诱导的认知缺陷均有减轻作用，这可能是通过其减轻神经炎症和增强生长因子信号通路的能力介导的。因此，它成为一种有前景的天然治疗剂，可用于管理疼痛及相关认知障碍。此外，支配认知和疼痛处理的相互交织的神经通路进一步凸显了口腔面部疼痛综合征的复杂性。
