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

ABSTRACT: Localized provoked vulvodynia is characterized by chronic vulvar pain that disrupts every aspect of the patient's life. Pain is localized to the vulvar vestibule, a specialized ring of tissue immediately surrounding the vaginal opening involved in immune defense. In this article, we show inflammation is the critical first step necessary for the generation of pain signals in the vulva. Inflammatory stimuli alone or combined with the transient receptor potential cation channel subfamily V member 4 (TRPV4) agonist 4α-phorbol 12,13-didecanoate stimulate calcium flux into vulvar fibroblast cells. Activity is blocked by the TRPV4 antagonist HC067047, denoting specificity to TRPV4. Using lipidomics, we found pro-resolving lipids in the vulvar vestibule were dysregulated, characterized by a reduction in pro-resolving mediators and heightened production of inflammatory mediators. We demonstrate specialized pro-resolving mediators represent a potential new therapy for vulvar pain, acting on 2 key parts of the disease mechanism by limiting inflammation and acutely inhibiting TRPV4 signaling.

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

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.

Prospective Association between Dysmenorrhea and Chronic Pain Development in Community-Dwelling Women.

Despite emerging evidence of associations between dysmenorrhea, enhanced pain sensitivity, and functional neuroimaging patterns consistent with chronic pain, it is unknown whether dysmenorrhea is prospectively associated with chronic pain development. Gaining a better understanding of this relationship could inform efforts in prevention of chronic pain. Using data from the national Midlife in the United States cohort, we examined the prospective association between dysmenorrhea and chronic pain development during a 10-year follow-up (starting 10 years after dysmenorrhea was measured) among 874 community-dwelling women aged 25-74 at baseline (when dysmenorrhea was measured). We fit modified Poisson regression models adjusting for sociodemographic, lifestyle and psychosocial factors. Among women who were menstruating at baseline, self-reported dysmenorrhea was associated with a 41% greater (95% confidence interval [CI] = 6%-88%) risk of developing chronic pain. Women with dysmenorrhea also developed chronic pain in more body regions (≥3 regions vs 1-2 regions vs none, odds ratio [OR] = 1.77, 95% CI = 1.18-2.64) and experienced greater pain interference (high-interference vs low-interference vs none, OR = 1.73, 95% CI = 1.15-2.59). Among women who had stopped menstruation at baseline, we did not find evidence of an association between their history of dysmenorrhea and subsequent risk of chronic pain development. Results suggest dysmenorrhea may be a general risk factor for chronic pain development among menstruating women. PERSPECTIVE: This study supports the temporality of dysmenorrhea and chronic pain development in a national female sample. Dysmenorrhea was also associated with developing more widespread and disabling pain among women who were still menstruating. Early management of dysmenorrhea may reduce the development and severity of chronic pain in women, although further research is required to determine whether dysmenorrhea is a causal risk factor or a risk marker of chronic pain.

Couple Interventions for Chronic Pain: A Systematic Review.

OBJECTIVE: Couple interventions for chronic pain have been shown to more effectively reduce pain intensity for individuals with chronic pain (ICPs) than individual behavioral interventions or usual care. This systematic review identified randomized controlled trials of couple interventions to highlight strategies that could be incorporated into psychotherapy with ICPs and their romantic partners. METHODS: The authors identified articles reporting randomized controlled trials of couple interventions for chronic pain. Three databases were searched (ie, PubMed, Embase, and PsycInfo), resulting in 18 studies and 22 articles. RESULTS: Couple interventions resulted in statistically significant improvements in pain intensity compared with other conditions in 8% to 40% of the studies depending on the comparator group (i.e., control, individual intervention, another couple intervention), and in statistically significant improvements on a pain-related outcome compared with other conditions in 31% to 50% of the studies depending on the comparator group (ie, control, individual intervention, another couple intervention). Educating couples about pain was the most common strategy (83%). Jointly administered relaxation or meditation skills were included in nearly half of the interventions (48%). Many interventions taught cognitive-behavioral skills jointly to couples (39%) or to the ICP with partner encouragement (30%). Teaching couples how to request and provide assistance (30%), and encouraging partners to avoid reinforcing pain behaviors (39%), occurred frequently. ICPs and their partners were often asked to set goals (30%). DISCUSSION: This review outlined strategies included in couple interventions for chronic pain that are derived from the cognitive-behavioral therapy, acceptance and commitment therapy, and operant behavioral traditions, but delivered relationally. Therapists working with ICPs and their partners may integrate these strategies into their practice to help couples who are managing chronic pain.

Toll-Like Receptor Signaling Contributes to Proinflammatory Mediator Production in Localized Provoked Vulvodynia.

OBJECTIVES: Localized provoked vulvodynia (LPV) afflicts approximately 8% of women in the United States and represents a huge financial, physical, and psychological burden. Women with LPV experience intense pain localized to the vulvar vestibule (area immediately surrounding vaginal opening). We have identified mechanisms involved in the development of LPV whereby vulvar fibroblasts respond to proinflammatory stimuli to perpetuate an inflammatory response that causes pain. However, these mechanisms are not fully elucidated. Therefore, we explored the role of toll-like receptors (TLRs), a class of innate immune receptors that rapidly respond to microbial assaults. MATERIALS AND METHODS: To determine whether TLRs are expressed by vulvar fibroblasts and whether these contribute to proinflammatory mediator production and pain in LPV, we examined TLR expression and innate immune responses in fibroblasts derived from painful vestibular regions compared with nonpainful external vulvar regions. RESULTS: Human vulvar fibroblasts express functional TLRs that trigger production of inflammatory mediators associated with chronic pain. We focused on the TLR-7-imiquimod proinflammatory interaction, because imiquimod, a ligand of TLR-7, may exacerbate pain in women during treatment of human papillomavirus-associated disease. CONCLUSIONS: Human vulvar fibroblasts express a broad spectrum of TLRs (a new finding). A significantly higher TLR-mediated proinflammatory response was observed in LPV case vestibular fibroblasts, and with respect to the imiquimod-TLR 7 interaction, development of chronic vestibular pain and inflammation may be a possible sequelae of treatment of vulvar human papillomavirus-associated disease. Suppressing enhanced TLR-associated innate immune responses to a spectrum of pathogen-associated molecular patterns may represent a new/effective therapeutic approach for vulvodynia.

A Role for Bradykinin Signaling in Chronic Vulvar Pain.

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.

Identification of novel mechanisms involved in generating localized vulvodynia pain.

OBJECTIVE: Our goal was to gain a better understanding of the inflammatory pathways affected during localized vulvodynia, a poorly understood, common, and debilitating condition characterized by chronic pain of the vulvar vestibule. STUDY DESIGN: In a control matched study, primary human fibroblast strains were generated from biopsies collected from localized provoked vulvodynia (LPV) cases and from age- and race-matched controls. We then examined intracellular mechanisms by which these fibroblasts recognize pathogenic Candida albicans; >70% of vulvodynia patients report the occurrence of prior chronic Candida infections, which is accompanied by localized inflammation and elevated production of proinflammatory/pain-associated interleukin (IL)-6 and prostaglandin E2 (PGE2). We focused on examining the signaling pathways involved in recognition of yeast components that are present and abundant during chronic infection. RESULTS: Dectin-1, a surface receptor that binds C albicans cell wall glucan, was significantly elevated in vestibular vs external vulvar cells (from areas without pain) in both cases and controls, while its abundance was highest in LPV cases. Blocking Dectin-1 signaling significantly reduced pain-associated IL-6 and PGE2 production during the response to C albicans. Furthermore, LPV patient vestibular cells produced inflammatory mediators in response to low numbers of C albicans cells, while external vulvar fibroblasts were nonresponsive. Inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (proinflammatory transcription factor) nearly abrogated IL-6 and PGE2 production induced by C albicans, in keeping with observations that Dectin-1 signals through the nuclear factor kappa-light-chain-enhancer of activated B cells pathway. CONCLUSION: These findings implicate that a fibroblast-mediated proinflammatory response to C albicans contributes to the induction of pain in LPV cases. Targeting this response may be an ideal strategy for the development of new vulvodynia therapies.