Exploring Localized Provoked Vulvodynia: Insights from Animal Model Research.

Provoked vulvodynia represents a challenging chronic pain condition, characterized by its multifactorial origins. The inherent complexities of human-based studies have necessitated the use of animal models to enrich our understanding of vulvodynia's pathophysiology. This review aims to provide an exhaustive examination of the various animal models employed in this research domain. A comprehensive search was conducted on PubMed, utilizing keywords such as "vulvodynia", "chronic vulvar pain", "vulvodynia induction", and "animal models of vulvodynia" to identify pertinent studies. The search yielded three primary animal models for vulvodynia: inflammation-induced, allergy-induced, and hormone-induced. Additionally, six agents capable of triggering the condition through diverse pathways were identified, including factors contributing to hyperinnervation, mast cell proliferation, involvement of other immune cells, inflammatory cytokines, and neurotransmitters. This review systematically outlines the various animal models developed to study the pathogenesis of provoked vulvodynia. Understanding these models is crucial for the exploration of preventative measures, the development of novel treatments, and the overall advancement of research within the field.

Is Vulvodynia Associated With an Altered Vaginal Microbiota?: A Systematic Review.

INTRODUCTION: Vulvodynia is defined as vulvar pain of at least 3 months' duration, without clear identifiable cause, which may have potential associated factors. It can have a significant impact on women's quality of life due to a combination of physical pain, emotional distress, and limited treatment options. Despite affecting a considerable number of women worldwide, the causes and underlying mechanisms of vulvodynia remain poorly understood. Given the recognized association of the vaginal microbiota with various gynecologic disorders, there has been growing interest in exploring the potential role of the vaginal microbiota in the etiology of vulvodynia. This systematic review aims to evaluate the current literature on the association between the vaginal microbiota and vulvodynia. MATERIAL AND METHODS: A systematic search of multiple databases, including PubMed, Scopus, Web of Science, Cochrane Library, and Ovid MEDLINE, was conducted to identify relevant peer-reviewed studies up to May 12, 2023. The following search terms were used across these databases: "vulvodynia," "vestibulodynia," "vulvar vestibulitis," "microbiome," "microbiota," and "flora." RESULTS: A total of 8 case-control studies were included, the quality of which was assessed using the Newcastle-Ottawa Scale. Data extraction and synthesis were performed using a standardized protocol. In most studies, no major differences were found between the vaginal bacterial composition of women with vulvodynia and that of controls. No specific bacterial taxa were consistently associated with vulvodynia. The relationship between vaginal microbiota diversity and vulvodynia remains to be fully understood. CONCLUSIONS: The role of vaginal microbiota in vulvodynia, if any, remains unclear. Because of the cross-sectional nature of the included studies, it is not possible to make any causal inferences. Further research, using larger and more diverse study populations and advanced sequencing techniques, is necessary to gain a better understanding of the potential relationship between the vaginal microbiota and vulvodynia.

Hyperbaric Oxygen Therapy Alleviates Memory and Motor Impairments Following Traumatic Brain Injury via the Modulation of Mitochondrial-Dysfunction-Induced Neuronal Apoptosis in Rats.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in young adults, characterized by primary and secondary injury. Primary injury is the immediate mechanical damage, while secondary injury results from delayed neuronal death, often linked to mitochondrial damage accumulation. Hyperbaric oxygen therapy (HBOT) has been proposed as a potential treatment for modulating secondary post-traumatic neuronal death. However, the specific molecular mechanism by which HBOT modulates secondary brain damage through mitochondrial protection remains unclear. Spatial learning, reference memory, and motor performance were measured in rats before and after Controlled Cortical Impact (CCI) injury. The HBOT (2.5 ATA) was performed 4 h following the CCI and twice daily (12 h intervals) for four consecutive days. Mitochondrial functions were assessed via high-resolution respirometry on day 5 following CCI. Moreover, IHC was performed at the end of the experiment to evaluate cortical apoptosis, neuronal survival, and glial activation. The current result indicates that HBOT exhibits a multi-level neuroprotective effect. Thus, we found that HBOT prevents cortical neuronal loss, reduces the apoptosis marker (cleaved-Caspase3), and modulates glial cell proliferation. Furthermore, HBO treatment prevents the reduction in mitochondrial respiration, including non-phosphorylation state, oxidative phosphorylation, and electron transfer capacity. Additionally, a superior motor and spatial learning performance level was observed in the CCI group treated with HBO compared to the CCI group. In conclusion, our findings demonstrate that HBOT during the critical period following the TBI improves cognitive and motor damage via regulating glial proliferation apoptosis and protecting mitochondrial function, consequently preventing cortex neuronal loss.

HBO treatment enhances motor function and modulates pain development after sciatic nerve injury via protection the mitochondrial function.

BACKGROUND: Peripheral nerve injury can cause neuroinflammation and neuromodulation that lead to mitochondrial dysfunction and neuronal apoptosis in the dorsal root ganglion (DRG) and spinal cord, contributing to neuropathic pain and motor dysfunction. Hyperbaric oxygen therapy (HBOT) has been suggested as a potential therapeutic tool for neuropathic pain and nerve injury. However, the specific cellular and molecular mechanism by which HBOT modulates the development of neuropathic pain and motor dysfunction through mitochondrial protection is still unclear. METHODS: Mechanical and thermal allodynia and motor function were measured in rats following sciatic nerve crush (SNC). The HBO treatment (2.5 ATA) was performed 4 h after SNC and twice daily (12 h intervals) for seven consecutive days. To assess mitochondrial function in the spinal cord (L2-L6), high-resolution respirometry was measured on day 7 using the OROBOROS-O2k. In addition, RT-PCR and Immunohistochemistry were performed at the end of the experiment to assess neuroinflammation, neuromodulation, and apoptosis in the DRG (L3-L6) and spinal cord (L2-L6). RESULTS: HBOT during the early phase of the SNC alleviates mechanical and thermal hypersensitivity and motor dysfunction. Moreover, HBOT modulates neuroinflammation, neuromodulation, mitochondrial stress, and apoptosis in the DRG and spinal cord. Thus, we found a significant reduction in the presence of macrophages/microglia and MMP-9 expression, as well as the transcription of pro-inflammatory cytokines (TNFa, IL-6, IL-1b) in the DRG and (IL6) in the spinal cord of the SNC group that was treated with HBOT compared to the untreated group. Notable, the overexpression of the TRPV1 channel, which has a high Ca2+ permeability, was reduced along with the apoptosis marker (cleaved-Caspase3) and mitochondrial stress marker (TSPO) in the DRG and spinal cord of the HBOT group. Additionally, HBOT prevents the reduction in mitochondrial respiration, including non-phosphorylation state, ATP-linked respiration, and maximal mitochondrial respiration in the spinal cord after SNC. CONCLUSION: Mitochondrial dysfunction in peripheral neuropathic pain was found to be mediated by neuroinflammation and neuromodulation. Strikingly, our findings indicate that HBOT during the critical period of the nerve injury modulates the transition from acute to chronic pain via reducing neuroinflammation and protecting mitochondrial function, consequently preventing neuronal apoptosis in the DRG and spinal cord.

Predisposition to cortical neurodegenerative changes in brains of hypertension prone rats.

BACKGROUND: Substantial evidence suggests that hypertension is a significant risk factor for cognitive decline. However, it is unclear whether the genetic predisposition to hypertension is also associated with cellular dysfunction that promotes neurodegeneration. METHODS: Changes in blood pressure were evaluated following dietary salt-loading or administration of a regular diet in Sabra Normotensive (SBN/y) and Sabra Hypertension-prone rats (SBH/y). We performed quantitative RT-PCR and immunofluorescence staining in brain cortical tissues before salt loading and 6 and 9 months after salt loading. To examine the expression of brain cortical proteins involved in the gene regulation (Histone Deacetylase-HDAC2; Histone Acetyltransferase 1-HAT1), stress response (Activating Transcription Factor 4-ATF4; Eukaryotic Initiation Factor 2- eIF2α), autophagy (Autophagy related 4A cysteine peptidase- Atg4a; light-chain 3-LC3A/B; mammalian target of rapamycin complex 1- mTORC1) and apoptosis (caspase-3). RESULTS: Prior to salt loading, SBH/y compared to SBN/y expressed a significantly higher level of cortical HAT1 (protein), Caspase-3 (mRNA/protein), LC3A, and ATF4 (mRNA), lower levels of ATG4A (mRNA/protein), LC3A/B, HDAC2 (protein), as well as a lower density of cortical neurons. Following dietary salt loading, SBH/y but not SBN/y developed high blood pressure. In hypertensive SBH/y, there was significant upregulation of cortical HAT1 (protein), Caspase-3 (protein), and eIF2α ~ P (protein) and downregulation of HDAC2 (protein) and mTORC1 (mRNA), and cortical neuronal loss. CONCLUSIONS: The present findings suggest that genetic predisposition to hypertension is associated in the brain cortex with disruption in autophagy, gene regulation, an abnormal response to cellular stress, and a high level of cortical apoptosis, and could therefore exacerbate cellular dysfunction and thereby promote neurodegeneration.

Blocking the ErbB pathway during adolescence affects the induction of anxiety-like behavior in young adult maternal immune activation offspring.

Epidemiological and experimental evidence demonstrates that maternal exposure to infection during gestation increases the offspring's risk of developing schizophrenia and other neurodevelopmental disorders. In addition, the NRG-ErbB4 signaling pathway is involved in brain development and neuropsychiatric disorders. Specifically, this pathway modulates the dopaminergic and GABAergic systems and is expressed in the early stages of prenatal development. We recently demonstrated that maternal immune activation (MIA) at late gestation altered the expression of NRG1, its receptor ErbB4, and the dopamine D2 receptor four hours post-injection of viral or LPS in the fetal brain. We also reported that blocking the ErbB pathway during adolescence resulted in increased striatal DA content and reduced preference for sweetness and alcohol that persists into adulthood. However, the combined effects of MIA, re-activation of the immune system, and disruption of the ErbB signaling during adolescence would affect young adult mice's behavioral phenotype is unknown. Here, we report that the expression levels of the NRG1, ErbB4, GAD67, and BDNF were changed as responses to MIA and blocked the ErbB signaling in the frontal cortex of adolescent mice. MIA-Offspring during late gestation and immune system re-activation during adolescence spent less time in the open arms of the elevated plus-maze in adulthood. At the same time, MIA-offspring administrated with the pan-ErbB inhibitor during adolescence spent the same amount of time in the opened arm as the control mice. Combining the ErbB signaling disruption during adolescence leads to a social interaction impairment in female offspring, but not male, without affecting the offspring's motor activity, long-term recognition, and working memory. These results imply that blocking the ErbB signaling during adolescence prevents the development of anxiety-like behavior of the MIA offspring later in life and suggest that this interaction does not reduce the risk of female MIA offspring developing impaired social behavior.

Changes in the Vaginal Microbiota of Women With Secondary Localized Provoked Vulvodynia.

OBJECTIVE: The etiology of localized provoked vulvodynia (LPV) remains unknown, but observations suggest the involvement of the vaginal microbiota. We examined the vaginal microbiota of women with LPV and healthy controls, upon after a low-oxalate diet (LOD). MATERIALS AND METHODS: A total of 9 women diagnosed with secondary LPV and 21 healthy controls were recruited from the Galilee Medical Center in Israel and subjected to prospective evaluations of their vaginal microbiota. Total DNA was extracted from vaginal discharge samples provided before and after following LOD for 3 weeks and was then subjected to 16S sequencing. Data obtained were then used to evaluate α and ß diversity, identify differentially abundant bacterial taxa in LPV, and determine their impact on the metabolism. RESULTS: These evaluations revealed decreased diversity in the vaginal microbiota of women with LPV and identified the Ochrobactrum genus and Pseudomonadaceae family as indicators for LPV. In addition, we identified 23 differentially expressed bacterial metabolic pathways between the LPV and control samples and revealed that LOD could induce changes in the ß diversity of LPV vaginal microbiomes, which was further supported by some degree of pain reduction in patients. CONCLUSIONS: Localized provoked vulvodynia and LOD were associated with shifts in the vaginal microbiota. However, the impact of these changes on the development of LPV requires additional studies with a larger cohort.

Characterization of Early Inflammatory Events Leading to Provoked Vulvodynia Development in Rats.

Background: Provoked vulvodynia (PV) is the main cause of vulvar pain and dyspareunia. The etiology of PV has not yet been elucidated. However, PV is associated with a history of recurrent inflammation, and its often accompanied by increases in the numbers of mast cells (MCs) and sensory hyperinnervation in the vulva. Therefore, this study aimed to examine the role of MCs and the early inflammatory events in the development of chronic vulvar pain in a rat model of PV. Methods: Mechanical and thermal vulvar sensitivity was measured for 5 months following zymosan vulvar challenges. Vulvar changes in glutamate and nerve growth factor (NGF) were analyzed using ELISA. Immunofluorescence (IF) staining of the vulvar section after 20, 81, and 160 days of the zymosan challenge were performed to test MCs accumulation, hyperinnervation, and expression of pain channels (transient receptor potential vanilloid/ankyrin-1-TRPV1 & TRPA1) in vulvar neurons. Changes in the development of vulvar pain were evaluated following the administration of the MCs stabilizer ketotifen fumarate (KF) during zymosan vulvar challenges. Results: Zymosan-challenged rats developed significant mechanical and thermal vulvar sensitivity that persisted for over 160 days after the zymosan challenge. During inflammation, increased local concentrations of NGF and glutamate and a robust increase in MCs degranulation were observed in zymosan-challenged rats. In addition, zymosan-challenged rats displayed sensory hyperinnervation and an increase in the expression of TRPV1 and TRPA1. Treatment with KF attenuated the upregulated level of NGF during inflammation, modulated the neuronal modifications, reduced MCs accumulation, and enhanced mechanical hypersensitivity after repeated inflammation challenges. Conclusion: The present findings suggest that vulvar hypersensitivity is mediated by MCs accumulation, nerve growth, and neuromodulation of TRPV1 and TRPA1. Hence, KF treatment during the critical period of inflammation contributes to preventing chronic vulvar pain development.