Sex dimorphism in pain threshold and neuroinflammatory response: the protective effect of female sexual hormones on behavior and seizures in an allergic rhinitis model
Research Report: The Protective Role of Gender on Pain Threshold and Neuroinflammatory Response in Allergic Rhinitis Model
Background Introduction
Allergic rhinitis (AR) is an inflammation of the nasal mucosa caused by allergens, affecting approximately 40% of the global population. Rhinitis not only causes physical discomfort but is also often accompanied by psychological disorders and reduced social function (Kremer et al., 2002). Studies have indicated that allergic rhinitis is closely linked to neurological and psychological disorders such as depression and anxiety, and even neurodegenerative diseases like Alzheimer’s disease and epilepsy (Oh et al., 2018; Lin et al., 2014).
Previous research has found that allergic rhinitis can induce behavioral changes and neuroinflammation in the hippocampus of male mice, affecting the nervous system through the TLR4/NF-κB pathway (Ebrahim et al., 2022). However, due to the complex influence of hormonal cycles on female mice in behavioral experiments, research has mostly focused on male subjects. This study aims to explore whether these findings are also universal in female mice and to further investigate the potential role of sex hormones in regulating the allergic model.
Research Source
This study was jointly authored by Mohammad Elahi, Zahra Ebrahim Soltani, Arya Afrooghe, Elham Ahmadi, and Ahmad Reza Dehpour from the Experimental Medicine Research Center and Interdisciplinary Research Center at Tehran University of Medical Sciences, Iran. The research was published in the Journal of Neuroimmune Pharmacology, Volume 19, 2024.
Research Process
This study aimed to reveal the effects of allergic rhinitis on behavior and neuroinflammation in female mice, involving the following key steps:
1. Mouse Grouping
The study used 36 male BALB/c mice and 72 female BALB/c mice. Female mice were randomly divided into four groups: female control group, female allergic rhinitis group, ovariectomy control group, and post-ovariectomy allergic rhinitis group. Male mice were divided into two groups for control and allergic rhinitis model testing.
2. Establishment of Allergic Rhinitis Model
Ovalbumin was injected intraperitoneally as an antigen and instilled intranasally to induce allergic rhinitis in mice. The control group was injected with saline at the same time points.
3. Ovariectomy
Ovariectomy was performed to eliminate the influence of estrogen. Food was restricted 12 hours before surgery, and behavioral tests were conducted after the procedure.
4. Behavioral Tests
A series of behavioral tests were conducted, such as the forced swimming test, hot plate test, von Frey fiber test, etc., to assess pain thresholds, anxiety, and depressive behaviors in mice.
5. Tissue Sampling and Molecular Detection
After behavioral tests, hippocampus and dorsal root ganglion tissues were collected from mice for RT-PCR, Western Blot, and ELISA detection to evaluate changes at the gene and protein levels.
Main Research Findings
1. Nasal Scratching Behavior and IgE Levels
Nasal scratching behavior and IgE levels showed significant increases in all allergic groups (female, post-ovariectomy female, male) compared to control groups.
2. Female Mice Without Ovariectomy
Although female mice showed decreased pain thresholds in pain tests, there were no significant differences in learning and memory, depression, and anxiety behavioral tests. This suggests that estrogen may have a protective effect on these behaviors.
3. Post-Ovariectomy Mice
Ovariectomized mice showed significant changes in behavior and neuroinflammation similar to male mice, including learning and memory impairment, anxiety and depressive-like behaviors, and lower seizure thresholds. This indicates that after the elimination of sex hormones, mice become more sensitive to neuroinflammation and behavioral changes caused by allergies.
4. Molecular Mechanisms
At the molecular level, the TLR4/NF-κB pathway and related inflammatory factors (such as IL-1β, IL-6, and TNF-α) did not show significant increases in expression in female allergic mice. In contrast, these factors increased significantly in post-ovariectomy allergic mice. Additionally, the expression of DNMT1 (DNA methyltransferase 1) decreased in female allergic mice but increased in post-ovariectomy mice. These findings suggest that DNMT1 may be involved in the regulation of sex hormones and inflammatory responses by modulating SOCS1 (Suppressor of Cytokine Signaling 1).
5. Relationship Between Sex Hormones and Pain
Female mice showed significantly reduced pain thresholds, and IL-17 and IL-23 levels in the DRG (dorsal root ganglion) were significantly increased, suggesting that sex hormones play an important role in pain signaling and neuroinflammation by regulating these factors. After ovariectomy, the expression levels of IL-17 and IL-23 returned to normal, while control male mice showed no significant changes.
Conclusion and Significance
This study demonstrates that sex hormones play an important protective role in regulating behavior and neuroinflammation caused by allergic rhinitis. The presence of sex hormones mitigates neuroinflammation and related neurobehavioral disorders, while their elimination makes mice more susceptible to allergy-induced neurobehavioral changes. These findings reveal the importance of sexual dimorphism in allergic diseases and highlight the need to consider gender-specific differences in future treatment strategy development, especially the regulatory role of sex hormones in the interaction between the immune and nervous systems.
This research emphasizes the importance of understanding the complex relationship between sex hormones, neuroinflammation, and behavior, and may provide new insights and therapeutic targets for the treatment of allergic rhinitis and its related complications.