Inflammation-induced mast cell-derived nerve growth factor: a key player in chronic vulvar pain?

Provoked vulvodynia (PV) is characterized by localized chronic vulvar pain. It is associated with a history of recurrent inflammation, mast cell (MC) accumulation, and neuronal sprouting in the vulva. However, the mechanism of how vulvar-inflammation promotes neuronal sprouting and gene-expression adaptation in the spinal cord, leading to hypersensitivity and painful sensations, is unknown. Here, we found that vulvar tissue from women with PV (n=8) is characterized by MC accumulation and neuronal sprouting compared to women without PV (n=4). In addition, we observed these changes in an animal study of PV. Thus, we found that repeated vulvar zymosan-inflammation challenges lead to long-lasting mechanical and thermal vulvar hypersensitivity, which was mediated by MC accumulation, neuronal sprouting, overexpression of the pain channels (TRPV1 and TRPA1) in vulvar neurons, as well as a long-term increase of gene expression related to neuroplasticity, neuroinflammation, and nerve growth factor (NGF) in the spinal cord/DRG(L6-S3). However, regulation of the NGF pathway by stabilization of MC activity with ketotifen fumarate (KF) during vulvar inflammation attenuated the local increase of NGF and histamine, as well as the elevated transcription of pro-inflammatory cytokines, and NGF pathway in the spinal cord. Additionally, KF treatment during inflammation modulates MC accumulation, neuronal hyperinnervation, and overexpression of the TRPV1 and TRPA1 channels in the vulvar neurons, consequently preventing the development of vulvar pain. A thorough examination of the NGF pathway during inflammation revealed that blocking NGF activity by using an NGF-non-peptide-inhibitor (Ro08-2750) regulates the upregulation of genes related to neuroplasticity, and NGF pathway in the spinal cord, as well as modulates neuronal sprouting and overexpression of the pain channels, resulting in a reduced level of vulvar hypersensitivity. On the other hand, stimulation of the NGF pathway in the vulvar promotes neuronal sprouting, overexpression of pain channels, and increase of gene expression related to neuroplasticity, neuroinflammation, and NGF in the spinal cord, resulting in long-lasting vulvar hypersensitivity. In conclusion, our findings suggest that vulvar allodynia induced by inflammation is mediated by MC accumulation, neuronal sprouting, and neuromodulation in the vulvar. Additionally, chronic vulvar pain may involve a long-term adaptation in gene expression in the spinal cord, which probably plays a critical role in central sensitization and pain maintenance. Strikingly, regulating the NGF pathway during the critical period of inflammation prevents vulvar pain development via modulating the neuronal changes in the vestibule and spinal cord, suggesting a fundamental role for the NGF pathway in PV development.

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.

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.