CD4-Positive T-Cell Recruitment in Primary-Provoked Localized Vulvodynia

Leclair, Catherine M.; Leeborg, Nicky; Jacobson‐Dunlop, Erick; Goetsch, Martha F.; Morgan, Terry K.

doi:10.1097/lgt.0b013e3182a55591

Cited by 30 publications

(32 citation statements)

References 24 publications

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“…Concordant with prior findings, numbers of T-cells, B-cells and macrophages were elevated 12, 33 . Interestingly, while some groups have reported substantial increases in mast cell presence within painful vestibular zones 10, 13 , our findings did not support a proliferation of this cell type.…”

Section: Discussionsupporting

confidence: 89%

“…For example, accumulations of T-cells 12, 33 with smaller numbers of B-cells and monocytes 12 have been reported. While some investigators note increased numbers of mast cells 10, 13 others do not 33, 41 , and some failed to find any evidence of inflammatory cell infiltration 18 . Hence, while the preponderance of evidence suggests that vestibular pain correlates with axonal and inflammatory cell proliferation, questions remain as to the nature, degree and significance of these changes.…”

Section: Introductionmentioning

confidence: 99%

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A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia

Liao

Chakrabarty

et al. 2017

The Journal of Pain

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Vestibulodynia is a form of provoked vulvodynia characterized by profound tenderness, hyperinnervation, and frequently inflammation within well-defined areas of the human vestibule. Prior experiments in animal models show that inflammatory hypersensitivity and hyperinnervation occur in concert with establishment of a local renin-angiotensin system (RAS). Moreover, mechanical hypersensitivity and sensory axon sprouting are prevented by blocking effects of angiotensin II on AT2 receptors. This case-control study assessed whether a RAS contributes to hyperinnervation observed in human vestibulodynia. Vestibular biopsies from asymptomatic controls or patients’ nontender areas showed moderate innervation and small numbers of inflammatory cells. In women with vestibulodynia, tender areas contained increased numbers of mechanoreceptive nociceptor axons, T-cells, macrophages and B-cells, while mast cells were unchanged. RAS proteins were increased due to greater numbers of T-cells and B-cells expressing angiotensinogen, and increased renin-expressing T-cells and macrophages. Chymase, which converts angiotensin I to angiotensin II, was present in constant numbers of mast cells. To determine if tender vestibular tissue generates angiotensin II that promotes axon sprouting, we conditioned culture medium with vestibular tissue. Rat sensory neurons cultured in control-conditioned medium showed normal axon outgrowth, while those in tender tissue-conditioned medium showed enhanced sprouting that was prevented by adding an AT2 antagonist or angiotensin II neutralizing antibody. Hypersensitivity in provoked vestibulodynia is therefore characterized by abnormal mechano-nociceptor axon proliferation, which is attributable to inflammatory cell-derived angiotensin II (or a closely related peptide) acting on neuronal AT2 receptors. Accordingly, reducing inflammation or blocking AT2 represent rational strategies to mitigate this common pain syndrome. Perspective: This study provides evidence that local inflammation leads to angiotensin II formation which acts on the angiotensin II receptor type 2 to induce nociceptor axon sprouting in vulvodynia. Preventing inflammation and blocking AT2 therefore present potential pharmacological strategies for reducing vestibular pain.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia

Liao

Chakrabarty

et al. 2017

The Journal of Pain

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“…Although the pathogenesis of LPV remains unidentified, a number of co-morbid conditions are associated with LPV symptoms, including recurrent fungal vulvovaginitis, a history of sexual or physical abuse, contact dermatitis, fibromyalgia, interstitial cystitis, surgical trauma or traumatic childbirth, pelvic floor dysfunction, gene polymorphisms, and inflammation 2,18, 20, 21, 23, 26, 28, 42, 46, 65, 68, 69 . Of these potential triggers, increasing evidence points to inflammation as a predominant instigator of vulvodynia 20, 23–25, 42, 65, 68 .…”

Section: Discussionmentioning

confidence: 99%

“…Of these potential triggers, increasing evidence points to inflammation as a predominant instigator of vulvodynia 20, 23–25, 42, 65, 68 . Inflammation is also a common catalyst in many other chronic pain conditions that lack discernable physical causes 71 .…”

Section: Discussionmentioning

confidence: 99%

A Role for Bradykinin Signaling in Chronic Vulvar Pain

Falsetta

Foster

Woeller

et al. 2016

The Journal of Pain

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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 NFκB signaling (a major inflammatory pathway), while 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/pro-pain stimuli, we move closer to understanding the origins of chronic vulvar pain and identifying new therapeutic targets, knowledge which could significantly improve patient care.

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“…Localized inflammation [27; 46], altered vestibular innervation [35], and tonic, dysfunctional pelvic floor muscle contractions have been implicated as possible causes [55; 83]. …”

Section: Introductionmentioning

confidence: 99%

Disease-related differences in resting-state networks

Gupta

Rapkin

Gill

et al. 2015

Pain

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Localized provoked vulvodynia (LPVD) affects approximately 16% of the female population, but biological mechanisms underlying symptoms remain unknown. Like in other, often comorbid chronic pain disorders, altered sensory processing and modulation of pain, including central sensitization, dysregulation of endogenous pain modulatory systems, and attentional enhancement of pain perception have been implicated. The aim of this study was to test whether regions of interest showing differences in LPVD compared to healthy controls (HCs) in structural and evoked-pain neuroimaging studies, also show alterations in during rest compared to HCs and a chronic pain control group (irritable bowel syndrome, IBS). Functional magnetic resonance imaging was performed during resting state in 87 age-matched premenopausal females (29 LPVD, 29 HCs, 29 IBS). Group independent component analysis and general linear models were applied to investigate group differences in the intrinsic connectivity of regions comprising sensorimotor, salience, and default mode resting state networks. LPVD subjects showed substantial alterations in the intrinsic connectivity of these networks compared to HCs and IBS. The intrinsic connectivity of many of the regions showing group differences during rest were moderately associated with clinical symptom reports in LPVD. Findings were robust to controlling for affect and medication usage. The current findings indicate LPVD subjects have alterations in the intrinsic connectivity of regions comprising the sensorimotor, salience, and default mode networks. Although shared brain mechanisms between different chronic pain disorders have been postulated, the current findings suggest some alterations in functional connectivity may show disease specificity.

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CD4-Positive T-Cell Recruitment in Primary-Provoked Localized Vulvodynia

Cited by 30 publications

References 24 publications

A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia

A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia

A Role for Bradykinin Signaling in Chronic Vulvar Pain

Disease-related differences in resting-state networks

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