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

Inflammation, lipid dysregulation, and transient receptor potential cation channel subfamily V member 4 signaling perpetuate chronic vulvar pain

“…Zymosan, a proinflammatory yeast cell wall preparation (Millipore Sigma, St. Louis, MO), was used to induce sustained vulvar allodynia, measured by pain threshold testing as described previously. 34,36 During the phase 1 of the experiment, fifty-two 8-week-old female C57BL/6 mice (Jackson Laboratories, Bar Harbor, ME) were acquired and trained to facilitate electronic von Frey determination of vulvar pain thresholds, as previously detailed. 34 Once the mice held relatively still in the testing apparatus upon introduction to the cage, baseline mechanical sensitivity threshold testing began.…”

“…Overall, the painful vestibule seems to express receptors involved in inflammation and mechanical pain signaling more robustly than nonpainful areas. [30][31][32][33] To determine whether TRPV4 contributes to the inflammatory signaling associated with LPV, [30][31][32][33][34]39,41 we knocked down expression of TRPV4 using siRNA and then measured the amount of IL-6 and PGE 2 produced, which serve as surrogate measures of pain. 39 Knockdown of TRPV4 (confirmed through qRT-PCR) significantly decreased both PGE 2 and IL-6 levels (Fig.…”

“…Reducing the levels of these mediators should at least partially ameliorate pain signaling, [30][31][32][33][34]39 suggesting TRPV4 represents another target for LPV pain therapy. Of advantage, targeting TRPV4 poses minimal risk, 23,24,66,69,70 has no abuse potential, and may in fact reduce the potential for substance abuse.…”

“…Based on the current vulvodynia literature, inflammation is believed to play a key role in the disease mechanism and is present throughout the disease course; exogenous stimuli such as conserved pathogen-associated molecular patterns (PAMPs) or endogenous stimuli such as interleukin-1b (IL-1b) can stimulate this response. 1,8,13,[30][31][32][33][34]39,40,58,59,78,97,101,115 Therefore, we evaluated the effect of 4aPDD on cells either pretreated or concurrently treated with the inflammatory stimulator IL-1b. In cells pretreated overnight with IL-1b, calcium signaling activity was apparent with all doses of 4aPDD, with or without an additional IL-1b treatment (Fig.…”

“…10,26,64,91,105 In localized provoked vulvodynia (LPV), patients experience intense pain upon touch to the area surrounding the vaginal opening, known as the vulvar vestibule. [30][31][32][33][34]39,41 Sites only a few millimeters away are comparatively pain-free. Pain with nonpainful stimuli, or allodynia, is a common form of neuropathic pain.…”