G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California, Los Angeles, California; Brain Research Institute UCLA, Gonda (Goldschmied) Neuroscience and Genetics Research Center, Los Angeles, California.
G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California, Los Angeles, California.
J Pain. 2021 Dec;22(12):1586-1605. doi: 10.1016/j.jpain.2021.04.017. Epub 2021 May 23.
Provoked vestibulodynia (PVD) is a chronic pain disorder characterized by local hypersensitivity and severe pain with pressure localized to the vulvar vestibule. Despite decades of study, the lack of identified biomarkers has slowed the development of effective therapies. The primary aim of this study was to use metabolomics to identify novel biochemical mechanisms in vagina and blood underlying brain biomarkers and symptoms in PVD, thereby closing this knowledge gap. Using a cross-sectional case-control observational study design, untargeted and unbiased metabolomic profiling of vaginal fluid and plasma was performed in women with PVD compared to healthy controls. In women with PVD, we also obtained assessments of vulvar pain, vestibular and vaginal muscle tenderness, and 24-hour symptom intensity alongside resting-state brain functional connectivity of brain regions involved in pain processing and modulation. Compared to healthy controls, women with PVD demonstrated differences primarily in vaginal (but not plasma) concentrations of metabolites of the sphingolipid signaling pathways, suggesting localized effects in vagina and vulvar vestibule rather than systemic effects. Our findings reveal that dysregulation of sphingolipid metabolism in PVD is associated with increased vulvar pain and muscle tenderness, sexual dysfunction, and decreased functional connectivity strength in pain processing/modulatory brain regions. This data collectively suggests that alterations in sphingolipid signaling pathways are likely an important molecular biomarker in PVD that could lead to new targets for therapeutic intervention. PERSPECTIVE: This manuscript presents the results of a robust, unbiased molecular assessment of plasma and vaginal fluid samples in women with provoked vestibulodynia compared to healthy controls. The findings suggest that alterations in sphingolipid signaling pathways are associated with symptoms and brain biomarkers and may be an important molecular marker that could provide new targets for therapeutic intervention.
诱发性外阴疼痛（PVD）是一种慢性疼痛障碍，其特征是外阴前庭局部敏感和剧烈疼痛，伴有压力。尽管经过几十年的研究，缺乏已识别的生物标志物仍阻碍了有效治疗方法的发展。本研究的主要目的是使用代谢组学来确定 PVD 中阴道和血液中潜在的大脑生物标志物和症状的新生化机制，从而填补这一知识空白。采用横断面病例对照观察性研究设计，对 PVD 女性与健康对照组进行阴道液和血浆的非靶向和无偏代谢组学分析。在 PVD 女性中，我们还评估了外阴疼痛、外阴和阴道肌肉压痛以及 24 小时症状强度，以及参与疼痛处理和调节的脑区的静息态脑功能连接。与健康对照组相比，PVD 女性主要表现为阴道（而非血浆）中鞘脂信号通路代谢物浓度的差异，表明阴道和外阴前庭存在局部作用，而不是全身作用。我们的研究结果表明，PVD 中鞘脂代谢失调与外阴疼痛和肌肉压痛增加、性功能障碍以及疼痛处理/调节脑区的功能连接强度降低有关。这些数据共同表明，鞘脂信号通路的改变可能是 PVD 中的一个重要分子生物标志物，可能为治疗干预提供新的靶点。观点：本文介绍了一项针对患有诱发性外阴疼痛的女性与健康对照组的血浆和阴道液样本进行的稳健、无偏分子评估的结果。研究结果表明，鞘脂信号通路的改变与症状和大脑生物标志物有关，可能是一个重要的分子标志物，为治疗干预提供新的靶点。
