A Role for Bradykinin Signaling in Chronic Vulvar Pain

Abstract Chronic vulvar pain is alarmingly common in women of reproductive age and is often accompanied by psychological distress, sexual dysfunction, and a significant reduction in quality of life. Localized provoked vulvodynia (LPV) is associated with intense vulvar pain concentrated in the vulvar...

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Bibliographic Details
Published in:The journal of pain 2016-11, Vol.17 (11), p.1183-1197
Main Authors: Falsetta, Megan L, Foster, David C, Woeller, Collynn F, Pollock, Stephen J, Bonham, Adrienne D, Haidaris, Constantine G, Phipps, Richard P
Format: Article
Language:English
Subjects:
Adult
Anesthesia & Perioperative Care
bradykinin
Bradykinin - analogs & derivatives
Bradykinin - genetics
Bradykinin - metabolism
Bradykinin - pharmacology
Bradykinin Receptor Antagonists - pharmacology
Case-Control Studies
Cells, Cultured
Chronic Pain
cytokine
Dose-Response Relationship, Drug
Enzyme Inhibitors - pharmacology
Female
Fibroblast
Fibroblasts - drug effects
Fibroblasts - metabolism
Humans
inflammation
Interleukin-6 - metabolism
NF-kappa B - genetics
NF-kappa B - metabolism
Pain Medicine
Pelvic Pain - drug therapy
Pelvic Pain - metabolism
Pelvic Pain - pathology
Receptors, Bradykinin - genetics
Receptors, Bradykinin - metabolism
RNA, Messenger - metabolism
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
Signal Transduction - physiology
vulvodynia
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Summary:Abstract Chronic vulvar pain is alarmingly common in women of reproductive age and is often accompanied by psychological distress, sexual dysfunction, and a significant reduction in quality of life. Localized provoked vulvodynia (LPV) is associated with intense vulvar pain concentrated in the vulvar vestibule (area surrounding vaginal opening). To date, the origins of vulvodynia are poorly understood, and treatment for LPV manages pain symptoms, but does not resolve the root causes of disease. Until recently, no definitive disease mechanisms had been identified; our work indicates LPV has inflammatory origins, although additional studies are needed to understand LPV pain. Bradykinin signaling is one of the most potent inducers of inflammatory pain and is a candidate contributor to LPV. We report that bradykinin receptors are expressed at elevated levels in LPV patient versus healthy control vestibular fibroblasts, and patient vestibular fibroblasts produce elevated levels of proinflammatory mediators with bradykinin stimulation. Inhibiting expression of one or both bradykinin receptors significantly reduces proinflammatory mediator production. Finally, we determined that bradykinin activates nuclear factor (NF)κB signaling (a major inflammatory pathway), whereas inhibition of NFκB successfully ablates this response. These data suggest that therapeutic agents targeting bradykinin sensing and/or NFκB may represent new, more specific options for LPV therapy. Perspective There is an unmet need for the development of more effective vulvodynia therapies. As we explore the mechanisms by which human vulvar fibroblasts respond to proinflammatory/propain stimuli, we move closer to understanding the origins of chronic vulvar pain and identifying new therapeutic targets, knowledge that could significantly improve patient care.
ISSN:1526-5900
1528-8447
DOI:10.1016/j.jpain.2016.07.007