Characterization of Early Inflammatory Events Leading to Provoked Vulvodynia Development in Rats

Yaseen Awad-Igbaria; Shilo Dadon; Alon Shamir; Alejandro Livoff; Mark Shlapobersky; Jacob Bornstein; Eilam Palzur

doi:10.2147/JIR.S367193

Characterization of Early Inflammatory Events Leading to Provoked Vulvodynia Development in Rats

J Inflamm Res. 2022 Jul 11:15:3901-3923. doi: 10.2147/JIR.S367193. eCollection 2022.

Authors

Yaseen Awad-Igbaria^{1

2}, Shilo Dadon^{1

2}, Alon Shamir^{3

4}, Alejandro Livoff⁵, Mark Shlapobersky⁵, Jacob Bornstein^#^{1

2}, Eilam Palzur^#²

Affiliations

¹ Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.
² The Research Institute of Galilee Medical Center, Nahariya, Israel.
³ Psychobiology Research Laboratory, Mazor Mental Health Center, Akko, Israel.
⁴ The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
⁵ Pathology Department, Barzilai University Medical Center, Ashkelon, Israel.

^# Contributed equally.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: glutamate; hyperinnervation; inflammation; mast cell; nerve growth factor; provoked vulvodynia.

Grants and funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.