Chronic pain is associated with memory deficits clinically and in animal models. Similarly, interstitial cystitis/bladder pain syndrome (IC/BPS) afflicts patients with severe chronic pelvic pain and urinary dysfunction as well as cognitive effects including anxiety/depression and patient-reported memory deficits. In a genetic model of IC/BPS, mice deficient for the lipase acyloxyacyl hydrolase (AOAH) mimic key symptoms including rodent correlates of chronic pelvic pain and anxiety/depression. Recently, we observed that pelvic pain of female AOAH-deficient mice is associated with microglial activation in the prefrontal cortex and paraventricular nucleus, and pain is dependent upon microglia. Because chronic pain is associated with memory deficits and microglia support learning and memory, we hypothesized that chronic pelvic pain is associated with memory deficits in IC/BPS models. In the hippocampus, we observed microglia in the dentate gyrus of AOAH-deficient females that exhibited a hyper-ramified morphology with increased branching, number of endpoints, and process length. In contrast, dentate gyrus microglia of AOAH-deficient males had an amoeboid morphology. Using specific memory tests, female AOAH-deficient mice exhibited deficits in both spatial and recognition memory relative to wild type controls, whereas males had a modest phenotype. Depleting microglia pharmacologically with an antagonist of colony stimulating factor-1 receptor resolved the deficit in recognition memory but did not improve spatial memory in females and had no significant effect in males. Overall, these data suggest a role for microglial modulation of cognitive function in pelvic pain that is sex-specific and thus identify a potential target for treating cognitive symptoms in female patients.

Introduction Chronic pelvic pain is a prevalent and multifactorial condition that significantly impacts quality of life. Multimodal management strategies targeting different pain pathways may offer improved clinical outcomes. This exploratory study aimed to evaluate whether a structured multimodal pelvic floor rehabilitation protocol combining low-intensity shock wave therapy (LiSWT) and transcutaneous electrical nerve stimulation (TENS) was associated with pain reduction in women with refractory chronic pelvic pain. Methods This study was designed as a single-arm pre-post study without a control group. It was conducted in 44 women with refractory chronic pelvic pain. All participants underwent a structured pelvic floor rehabilitation program consisting of 12 weekly sessions. TENS was applied weekly, and LiSWT was administered in eight sessions during the treatment period. Pain severity was measured with the Visual Analog Scale (VAS) before initiation of therapy and after completion of the rehabilitation program. Pre- and post-treatment VAS scores were compared using a paired-samples t-test. Results Final analysis included 44 women with refractory chronic pelvic pain. Mean pain scores decreased from 9.3 before treatment to 1.2 after treatment, demonstrating a statistically significant reduction. Conclusion The combination of LiSWT and TENS was associated with a clinically meaningful short-term reduction in pain among women with refractory chronic pelvic pain. These preliminary findings support the potential role of multimodal therapeutic strategies targeting different mechanisms involved in chronic pain. Further randomized controlled studies with long-term follow-up are required to confirm these results, isolate the contribution of each modality, and evaluate the durability of response.

Endometriosis is an inflammatory gynecologic disease characterized by ectopic growth of endometrial-like tissue, resulting in pelvic pain and infertility. T-helper 9 (Th9) cells play a known role in various chronic inflammatory diseases. Despite parallels between endometriosis and Th9-driven diseases, their role in endometriosis has not been extensively explored. We investigated Th9 cell involvement in endometriosis pathophysiology using human tissue samples, in vitro experiments with human-derived Th9 cells, and in vivo experiments to shed insight on the impact of adoptively transferred Th9 cells in our established syngeneic endometriosis mouse model. Immunohistochemistry of a tissue microarray revealed significantly increased IL-9-positive cells in patient lesions compared to control endometrium. Human CD4+ Th cells purified from peripheral blood mononuclear cells treated with Th9-driving growth factors produced significantly altered proinflammatory mediators (increased IL-5 and IL-17F; decreased IL-8) in response to estrogen stimulation. Adoptive transfer of mouse Th9-like cells increased plasma IL-1α concentration and altered transcriptional profiles of several signaling pathways, including Notch and PI3K-Akt. Immunofluorescent microscopy depicted adoptively transferred Th9 cells present within mouse lesions. Furthermore, immunohistochemical analysis demonstrated reduced lesion proliferation following Th9 adoptive transfer. This study provides the first evidence that Th9 cells likely promote immune-inflammatory alterations within lesions to exacerbate disease.

Pain is influenced by a complex interplay of biological, psychological, and social factors. Sex has emerged as a key determinant of vulnerability to chronic pain and a major risk factor for poor response to available pharmacological treatments. Women report higher rates of chronic pain and exhibit greater pain sensitivity; however, the underlying mechanisms remain poorly understood. Preclinical models are essential to uncover sex-specific biological pathways involved in pain and to guide the development of novel, targeted therapies through translational approaches. This review summarizes animal models of female-associated pelvic pain disorders, including endometriosis, adenomyosis, dysmenorrhea, vulvodynia, interstitial cystitis, uterine leiomyomas, chronic pelvic pain, and pelvic inflammatory disease. These models recapitulate key features such as lesion biology, neuroimmune interactions, and pain behaviors also observed in patients. However, current models still face limitations in capturing spontaneous pain dynamics, hormonal complexity, and psychosocial influences. Refining and integrating biological, behavioral, and sex-specific endpoints will be crucial to enhance their translational relevance and advance precision pain therapies for women.