Liao Zhaohui, Chakrabarty Anuradha, Mu Ying, Bhattacherjee Aritra, Goestch Martha, Leclair Catherine M, Smith Peter G
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas.
Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon.
J Pain. 2017 May;18(5):511-525. doi: 10.1016/j.jpain.2016.12.008. Epub 2017 Jan 3.
Vestibulodynia is a form of provoked vulvodynia characterized by profound tenderness, hyperinnervation, and frequently inflammation within well-defined areas of the human vestibule. Previous experiments in animal models show that inflammatory hypersensitivity and hyperinnervation occur in concert with establishment of a local renin-angiotensin system (RAS). Moreover, mechanical hypersensitivity and sensory axon sprouting are prevented by blocking effects of angiotensin II on angiotensin II receptor type 2 (AT2) receptors. This case-control study assessed whether a RAS contributes to hyperinnervation observed in human vestibulodynia. Vestibular biopsies from asymptomatic controls or patients' nontender areas showed moderate innervation and small numbers of inflammatory cells. In women with vestibulodynia, tender areas contained increased numbers of mechanoreceptive nociceptor axons, T-cells, macrophages, and B-cells, whereas mast cells were unchanged. RAS proteins were increased because of greater numbers of T cells and B cells expressing angiotensinogen, and increased renin-expressing T cells and macrophages. Chymase, which converts angiotensin I to angiotensin II, was present in constant numbers of mast cells. To determine if tender vestibular tissue generates angiotensin II that promotes axon sprouting, we conditioned culture medium with vestibular tissue. Rat sensory neurons cultured in control-conditioned medium showed normal axon outgrowth, whereas those in tender tissue-conditioned medium showed enhanced sprouting that was prevented by adding an AT2 antagonist or angiotensin II neutralizing antibody. Hypersensitivity in provoked vestibulodynia is therefore characterized by abnormal mechanonociceptor axon proliferation, which is attributable to inflammatory cell-derived angiotensin II (or a closely related peptide) acting on neuronal AT2 receptors. Accordingly, reducing inflammation or blocking AT2 represent rational strategies to mitigate this common pain syndrome.
This study provides evidence that local inflammation leads to angiotensin II formation, which acts on the AT2 to induce nociceptor axon sprouting in vulvodynia. Preventing inflammation and blocking AT2 therefore present potential pharmacological strategies for reducing vestibular pain.
前庭痛是一种激发性外阴痛，其特征为在人类前庭的明确区域内有深度压痛、神经支配过度，且常伴有炎症。先前在动物模型中的实验表明，炎症超敏反应和神经支配过度与局部肾素-血管紧张素系统（RAS）的建立同时发生。此外，通过阻断血管紧张素II对2型血管紧张素II受体（AT2）的作用，可预防机械性超敏反应和感觉轴突发芽。本病例对照研究评估了RAS是否与人类前庭痛中观察到的神经支配过度有关。来自无症状对照者或患者非压痛区域的前庭活检显示神经支配适度且炎症细胞数量较少。在前庭痛女性中，压痛区域含有更多数量的机械感受性伤害性感受器轴突、T细胞、巨噬细胞和B细胞，而肥大细胞数量未变。由于表达血管紧张素原的T细胞和B细胞数量增加，以及表达肾素的T细胞和巨噬细胞增加，RAS蛋白增加。将血管紧张素I转化为血管紧张素II的糜酶，在恒定数量的肥大细胞中存在。为了确定压痛的前庭组织是否产生促进轴突发芽的血管紧张素II，我们用前庭组织处理培养基。在对照处理培养基中培养的大鼠感觉神经元显示正常的轴突生长，而在压痛组织处理培养基中培养的神经元显示出增强的发芽，添加AT2拮抗剂或血管紧张素II中和抗体可阻止这种发芽。因此，激发性前庭痛中的超敏反应的特征是机械性伤害性感受器轴突异常增殖，这归因于炎症细胞衍生的血管紧张素II（或密切相关的肽）作用于神经元AT2受体。因此，减轻炎症或阻断AT2是减轻这种常见疼痛综合征的合理策略。
本研究提供了证据表明局部炎症导致血管紧张素II形成，其作用于AT2以诱导外阴痛中的伤害性感受器轴突发芽。因此，预防炎症和阻断AT2是减轻前庭疼痛的潜在药理学策略。
