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

Tejada, Miguel; Santos-Llamas, Ana I.; Escriva, Lesley; Tarı́n, Juan J.; Cano, Antonio; Fernandez-Ramirez, Maria J.; Nunez-Badinez, Paulina; Leo, Bianca De; Saunders, Philippa T. K.; Vidal, Victor; Barthas, Florent; Vincent, Katy; Sweeney, Patrick J.; Sillito, Rowland R.; Armstrong, J. D.; Nagel, Jens; Gómez, Raúl

doi:10.3390/biomedicines10020501

Cited by 6 publications

(11 citation statements)

References 51 publications

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“…In this study, we were not able to detect any endometriosis-associated pain behavior in our animals. These results are comparable to other investigators who indicated that no significant difference could be observed in thermal sensitivity between the endometriosis and sham animals 46, 88 , although others do document the presence of endometriosis-related hyperalgesia in mice 16, 44, 80, 81, 85, 89–92 . This discrepancy in results could be related to differences in study set-up, and more specifically in the choice of the control group.…”

Section: Discussionsupporting

confidence: 89%

“…In our study, we implanted adipose tissue in the control animals and we showed that the mice implanted with menstrual endometrium and the control animals were comparable regarding tissue attachment, maintenance and nerve fiber innervation. Indeed, another study also showed limited differences in behavior between mice inoculated with endometrial tissue and mice implanted with adipose tissue 92 . Nevertheless, Castro et al 85 indicated that endometriosis mice displayed increased sensitivity to evoked pain measurements, while sham animals, with attached adipose tissue implants, did not show such behavior.…”

Section: Endometriosis-related Behaviormentioning

confidence: 99%

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Investigating endometriosis development and endometriosis-related pain over time and in relation to estrogen in a laparoscopic mouse model

Peterse,

Verhassel,

Fassbender

et al. 2024

Preprint

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Background: Endometriosis is a complex disease, and its pathophysiology is still unclear. Therefore, endometriosis animal models need to be carefully selected and examined to be useful for identification of novel therapies for women with endometriosis. In this study, we evaluated endometriosis-associated pain, and time- and estrogen-related development of endometriotic lesions after laparoscopic implantation of menstrual endometrium in a homologous mouse model for endometriosis. Methods: Endometriosis was induced by laparoscopic introduction of 10 menstrual endometrial tissue pieces into the peritoneum of ovariectomized recipient mice (59 estrogen-substituted; 59 estrogen-depleted). Sham animals (57 estrogen-substituted; 60 estrogen-depleted) received 10 pieces of perigonadal adipose tissue. The animals were sacrificed at 1, 2, 3, 4, 6 or 8 weeks after induction, the attached peritoneal implants localized and excised and immunohistochemically analyzed. Additionally, endometriosis-related pain was evaluated by measuring mechanical allodynia, thermal hyperalgesia, locomotor activity and anxiety-like behavior before and after tissue implantation. Results: At least one implant per mouse could be retrieved in 94% (111/118) of the endometrial tissue animals and in 78% (91/117) of the adipose tissue animals (p<0.001). Peritoneal implant take rate was significantly higher in endometrial tissue animals (2.5 +/- 1.4) compared to adipose tissue animals (1.6 +/- 1.5) (p<0.0001), regardless of estrogen supplementation and time of sacrifice. Hemosiderin could be observed more often (p<0.0001) in attached peritoneal implants of the endometrial tissue animals (67%, 68/101), compared to the adipose tissue animals (37%, 31/83). Ki67 staining showed a higher proliferation index in the attached peritoneal implants retrieved after one week, compared to the other time points of both endometrial tissue and adipose tissue animals. The behavioral test showed no significant difference in mechanical and thermal sensitivity, locomotor activity and anxiety-behavior between the menstrual endometrial tissue and adipose tissue implanted animals. Nevertheless, the estrogen-substituted animals showed decreased activity in the tests featuring thermal nociception and anxiety-like behavior, compared to the estrogen-depleted animals. Additionally, time after implantation showed to have a positive effect on thermal sensitivity, locomotor activity and anxiety-related behavior in all animals, as the mice became less sensitive to thermal stimuli, more active in the open field test and buried less marbles in the marble burying test. Conclusion: This study showed an increased attachment of menstrual endometrium compared to adipose tissue in the peritoneum when using laparoscopic induction. There was no apparent influence of estrogen on tissue attachment, proliferation or appearance. A decrease in cell proliferation in peritoneal implants occurred over time. Locomotor activity, anxiety-like behavior, and mechanical and thermal sensitivity of the animals was not affected after induction of endometriosis, regardless of the type of implanted tissue. Altogether, we showed that the current methodology used to induce endometriosis was not sufficient to develop endometriotic lesions that contained both stromal and epithelial cells. Moreover, the current methodology was not able to detect specific endometriosis-related pain.

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Section: Discussionsupporting

confidence: 89%

Section: Endometriosis-related Behaviormentioning

confidence: 99%

Investigating endometriosis development and endometriosis-related pain over time and in relation to estrogen in a laparoscopic mouse model

Peterse,

Verhassel,

Fassbender

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The heterologous model (xenograft) is obtained by implanting a portion of an endometrial biopsy from a human donor into an immunosuppressed mouse [52,53]. Although the implantation rate is around 30%, this percentage can increase to 100% when implants are sewn or glued using tissue adhesive [52].…”

Section: Heterologous Modelsmentioning

confidence: 99%

Rodent Animal Models of Endometriosis-Associated Pain: Unmet Needs and Resources Available for Improving Translational Research in Endometriosis

Tejada

Antunez

Nunez-Badinez

et al. 2023

IJMS

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Chronic pain induced by endometriosis is a maladaptive pain experienced by half of women with this disease. The lack of pharmacological treatments suitable for the long-term relief of endometriosis-associated pain, without an impact on fertility, remains an urgent unmet need. Progress has been slowed by the absence of a reproducible rodent endometriosis model that fully replicates human physiopathological characteristics, including pain symptoms. Although pain assessment in rodents is a complicated task requiring qualified researchers, the choice of the behavioral test is no less important, since selecting inappropriate tests can cause erroneous data. Pain is usually measured with reflex tests in which hypersensitivity is evaluated by applying a noxious stimulus, yet this ignores the associated emotional component that could be evaluated via non-reflex tests. We conducted a systematic review of endometriosis models used in rodents and the number of them that studied pain. The type of behavioral test used was also analyzed and classified according to reflex and non-reflex tests. Finally, we determined the most used reflex tests for the study of endometriosis-induced pain and the main non-reflex behavioral tests utilized in visceral pain that can be extrapolated to the study of endometriosis and complement traditional reflex tests.

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“…19), immunodeficient mice implanted with endometriotic lesions showed chronic pain behaviour but no significant difference in nerve density (Ref. 20). This also suggests that the mechanisms of pain associated with endometriosis are involved in an abnormality in the pain pathways with complicated pathogenesis.…”

Section: Neurogenesis and Endometriosismentioning

confidence: 99%

Unveil the pain of endometriosis: from the perspective of the nervous system

Fan

2022

Expert Rev. Mol. Med.

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Endometriosis is a chronic inflammatory disease with pelvic pain and uncharacteristic accompanying symptoms. Endometriosis-associated pain often persists despite treatment of the disease, thus it brings a deleterious impact on their personal lives as well as imposing a substantial economic burden on them. At present, mechanisms underlie endometriosis-associated pain including inflammatory reaction, injury, aberrant blood vessels and the morphological and functional anomaly of the peripheral and central nervous systems. The nerve endings are influenced by the physical and chemical factors surrounding the lesion, via afferent nerve to the posterior root of the spinal nerve, then to the specific cerebral cortex involved in nociception. However, our understanding of the aetiology and mechanism of this complex pain process caused by endometriosis remains incomplete. Identifying the pathogenesis of endometriosis is crucial to disease management, offering proper treatment, and helping patients to seek novel targets for the maintenance and contributors of chronic pain. The main aim of this review is to focus on every possible mechanism of pain related to endometriosis in both peripheral and central nervous systems, and to present related mechanisms of action from the interaction between peripheral lesions and nerves to the changes in transmission of pain, resulting in hyperalgesia and the corresponding alterations in cerebral cortex and brain metabolism.

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

Cited by 6 publications

References 51 publications

Investigating endometriosis development and endometriosis-related pain over time and in relation to estrogen in a laparoscopic mouse model

Investigating endometriosis development and endometriosis-related pain over time and in relation to estrogen in a laparoscopic mouse model

Rodent Animal Models of Endometriosis-Associated Pain: Unmet Needs and Resources Available for Improving Translational Research in Endometriosis

Unveil the pain of endometriosis: from the perspective of the nervous system

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