Awad-Igbaria Yaseen, Dadon Shilo, Shamir Alon, Livoff Alejandro, Shlapobersky Mark, Bornstein Jacob, Palzur Eilam
Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.
The Research Institute of Galilee Medical Center, Nahariya, Israel.
J Inflamm Res. 2022 Jul 11;15:3901-3923. doi: 10.2147/JIR.S367193. eCollection 2022.
Provoked vulvodynia (PV) is the main cause of vulvar pain and dyspareunia. The etiology of PV has not yet been elucidated. However, PV is associated with a history of recurrent inflammation, and its often accompanied by increases in the numbers of mast cells (MCs) and sensory hyperinnervation in the vulva. Therefore, this study aimed to examine the role of MCs and the early inflammatory events in the development of chronic vulvar pain in a rat model of PV.
Mechanical and thermal vulvar sensitivity was measured for 5 months following zymosan vulvar challenges. Vulvar changes in glutamate and nerve growth factor (NGF) were analyzed using ELISA. Immunofluorescence (IF) staining of the vulvar section after 20, 81, and 160 days of the zymosan challenge were performed to test MCs accumulation, hyperinnervation, and expression of pain channels (transient receptor potential vanilloid/ankyrin-1-TRPV1 & TRPA1) in vulvar neurons. Changes in the development of vulvar pain were evaluated following the administration of the MCs stabilizer ketotifen fumarate (KF) during zymosan vulvar challenges.
Zymosan-challenged rats developed significant mechanical and thermal vulvar sensitivity that persisted for over 160 days after the zymosan challenge. During inflammation, increased local concentrations of NGF and glutamate and a robust increase in MCs degranulation were observed in zymosan-challenged rats. In addition, zymosan-challenged rats displayed sensory hyperinnervation and an increase in the expression of TRPV1 and TRPA1. Treatment with KF attenuated the upregulated level of NGF during inflammation, modulated the neuronal modifications, reduced MCs accumulation, and enhanced mechanical hypersensitivity after repeated inflammation challenges.
The present findings suggest that vulvar hypersensitivity is mediated by MCs accumulation, nerve growth, and neuromodulation of TRPV1 and TRPA1. Hence, KF treatment during the critical period of inflammation contributes to preventing chronic vulvar pain development.
诱发性外阴痛（PV）是外阴疼痛和性交困难的主要原因。PV的病因尚未阐明。然而，PV与复发性炎症病史相关，且常伴有肥大细胞（MCs）数量增加和外阴感觉神经纤维增生。因此，本研究旨在探讨MCs和早期炎症事件在PV大鼠模型慢性外阴疼痛发展中的作用。
在酵母聚糖对外阴进行刺激后，持续5个月测量大鼠外阴的机械性和热敏感性。采用酶联免疫吸附测定法（ELISA）分析外阴中谷氨酸和神经生长因子（NGF）的变化。在酵母聚糖刺激20、81和160天后，对外阴切片进行免疫荧光（IF）染色，以检测MCs的积聚、神经纤维增生以及外阴神经元中疼痛通道（瞬时受体电位香草酸亚型1/锚蛋白1 - TRPV1和TRPA1）的表达。在酵母聚糖对外阴进行刺激期间，给予MCs稳定剂富马酸酮替芬（KF），评估外阴疼痛发展的变化。
酵母聚糖刺激的大鼠出现了显著的外阴机械性和热敏感性，在酵母聚糖刺激后持续超过160天。在炎症期间，酵母聚糖刺激的大鼠局部NGF和谷氨酸浓度升高，且MCs脱颗粒显著增加。此外，酵母聚糖刺激的大鼠表现出感觉神经纤维增生以及TRPV1和TRPA1表达增加。KF治疗减弱了炎症期间NGF上调水平，调节了神经元改变，减少了MCs积聚，并在反复炎症刺激后增强了机械性超敏反应。
目前的研究结果表明，外阴超敏反应是由MCs积聚、神经生长以及TRPV1和TRPA1的神经调节介导的。因此，在炎症关键期进行KF治疗有助于预防慢性外阴疼痛的发展。
