A mouse model of endometriosis that displays vaginal, colon, cutaneous, and bladder sensory comorbidities

Abstract

Endometriosis is a painful inflammatory disorder affecting ~10% of women of reproductive age. Although chronic pelvic pain (CPP) remains the main symptom of endometriosis patients, adequate treatments for CPP are lacking. Animal models that recapitulate the features and symptoms experienced by women with endometriosis are essential for investigating the etiology of endometriosis, as well as developing new treatments. In this study, we used an autologous mouse model of endometriosis to examine a combination of disease features and symptoms including: a 10 week time course of endometriotic lesion development; the chronic inflammatory environment and development of neuroangiogenesis within lesions; sensory hypersensitivity and altered pain responses to vaginal, colon, bladder, and skin stimulation in conscious animals; and spontaneous animal behavior. We found significant increases in lesion size from week 6 posttransplant. Lesions displayed endometrial glands, stroma, and underwent neuroangiogenesis. Additionally, peritoneal fluid of mice with endometriosis contained known inflammatory mediators and angiogenic factors. Compared to Sham, mice with endometriosis displayed: enhanced sensitivity to pain evoked by (i) vaginal and (ii) colorectal distension, (iii) altered bladder function and increased sensitivity to cutaneous (iv) thermal and (v) mechanical stimuli. The development of endometriosis had no effect on spontaneous behavior. This study describes a comprehensive characterization of a mouse model of endometriosis, recapitulating the clinical features and symptoms experienced by women with endometriosis. Moreover, it delivers the groundwork to investigate the etiology of endometriosis and provides a platform for the development of therapeutical interventions to manage endometriosis-associated CPP.

Clodronate Treatment Prevents Vaginal Hypersensitivity in a Mouse Model of Vestibulodynia

“…This is the first time that vulvovaginal sensitivity has been assessed in vivo using VMR to VD in a model of vaginal hyperinnervation, and it clearly discriminates CFA mice from control as well as clodronate-treated mice. Increased VMR elicited by vaginal distension has previously been demonstrated in adult mice following neonatal vaginal irritation (zymosan) and in rat and mouse models of endometriosis ( Nagabukuro and Berkley, 2007 ; Dmitrieva et al., 2012 ; Castro et al., 2021 ). The relatively small animal-to-animal variation shown in this study supports previous assertions VMR is a highly reproducible and reliable measure of visceral nociception ( Ness and Gebhart, 1988 ).…”

“…On day 7 we recorded the visceromotor response (VMR) to vaginal distension (VD) as an objective measurement of vaginal sensitivity to pain in fully conscious animals ( Berkley et al., 2007 ; Ge et al., 2019 ; Castro et al., 2021 ). Abdominal muscle contraction in response to non-noxious and noxious VD was quantified by recording the electrical activity (EMG) as previously described ( Castro et al., 2021 ).…”

“…ERK activation increases neuronal sensitivity to further inputs, mediating central sensitisation ( Ji et al., 1999 ; Gao and Ji, 2009 ). Another highly reproducible and reliable quantitative measure of visceral nociception is the visceromotor response (VMR) ( Ness and Gebhart, 1988 ), a nociceptive brainstem reflex in which noxious distension of hollow organs such as the vagina triggers contraction of abdominal muscles ( Berkley et al., 2007 ; Ge et al., 2019 ; Castro et al., 2021 ). Assessing pERK and VMR in our model will show whether the nociceptive signal sent from the periphery to the CNS is augmented, and whether this ultimately results in vaginal hypersensitivity associated with chronic pain.…”

Identification of Altered Evoked and Non-Evoked Responses in a Heterologous Mouse Model of Endometriosis-Associated Pain

“…While a range of preclinical homologous animal models have been used to better understand the etiology of endometriosis-associated pain, non-evoked tests for characterization of pain-like behaviors have been rarely used [ 34 , 49 , 50 , 51 ]. There has not been a single report (to our knowledge) employing heterologous models for such purpose and no apparent reason for such asymmetry in their use.…”

A syngeneic inoculation mouse model of endometriosis that develops multiple comorbid visceral and cutaneous pain like behaviours

“…Sections (10 mm) were stained with H&E by the University of Adelaide Histology Core Facility (Adelaide, South Australia) and histologically assessed to confirm the morphological presence of both epithelial glands and stromal cells, as previously described. 15,22,24 Biopsies that did not contain the morphology of endometrium were not included for any further neuroangiogenesis analysis.…”