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Specialized Pro-resolving Mediators Reduce Pro-nociceptive Inflammatory Mediator Production in Models of Localized Provoked Vulvodynia

      Highlights

      • Vulvodynia reduces a woman's quality of life, and new therapies are direly needed.
      • Inflammation likely plays a role in vulvodynia and represents a therapeutic target.
      • Agents that resolve inflammation reduce pro-nociceptive signals in human vulvar fibroblasts.
      • Pro-resolving agents have analgesic effects in a mouse model of vulvodynia.
      • Pro-resolving agents are a potentially noninvasive and safe therapy for vulvodynia.

      Abstract

      Localized provoked vulvodynia (LPV) is the most common cause of chronic dyspareunia in premenopausal women, characterized by pain with light touch to the vulvar vestibule surrounding the vaginal opening. The devastating impact of LPV includes sexual dysfunction, infertility, depression, and even suicide. Yet, its etiology is unclear. No effective medical therapy exists; surgical removal of the painful vestibule is the last resort. In LPV, the vestibule expresses a unique inflammatory profile with elevated levels of pro-nociceptive proinflammatory mediators prostaglandin E2 (PGE2) and interleukin-6 (IL-6), which are linked to lower mechanical sensitivity thresholds. Specialized pro-resolving mediators (SPMs), lipids produced endogenously within the body, hold promise as an LPV treatment by resolving inflammation without impairing host defense. Ten of 13 commercially available SPMs reduced IL-6 and PGE2 production by vulvar fibroblasts, administered either before or after inflammatory stimulation. Using a murine vulvar pain model, coupling proinflammatory mediator quantification with mechanical sensitivity threshold determination, topical treatment with the SPM, maresin 1, decreased sensitivity and suppressed PGE2 levels. Docosahexaenoic acid, a precursor of maresin 1, was also effective in reducing PGE2 in vulvar fibroblasts and rapidly restored mouse sensitivity thresholds. Overall, SPMs and their precursors may be a safe and efficacious for LPV.
      Perspective: Vulvodynia, like many pain conditions, is difficult to treat because disease origins are incompletely understood. Here, we applied our knowledge of more recently discovered vulvodynia disease mechanisms to screen novel therapeutics. We identified several specialized pro-resolving mediators as likely potent and safe for treating LPV with potential for broader application.

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